Fused Piperidine Amides as Modulators of Ion Channels

ABSTRACT

The invention relates to fused piperidine amides useful as inhibitors of ion channels for the treatment of pain. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/844,499, filed Jul. 10, 2013, the entire contents ofwhich are hereby incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of ion channels.The invention also provides pharmaceutically acceptable compositionscomprising the compounds of the invention and methods of using thecompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Voltage-gated sodium channels are believed to play a critical role inpain signaling. This belief is based on the known roles of thesechannels in normal physiology, pathological states arising frommutations in sodium channel genes, preclinical work in animal models ofdisease, and the clinical usefulness of known sodium channel modulatingagents (Cummins, T. R., Sheets, P. L., and Waxman, S. G., The roles ofsodium channels in nociception: Implications for mechanisms of pain.Pain 131 (3), 243 (2007); England, S., Voltage-gated sodium channels:the search for subtype-selective analgesics. Expert Opin Investig Drugs17 (12), 1849 (2008); Krafte, D. S. and Bannon, A. W., Sodium channelsand nociception: recent concepts and therapeutic opportunities. CurrOpin Pharmacol 8 (1), 50 (2008)).

Voltage-gated sodium channels (NaV's) are key biological mediators ofelectrical signaling. NaV's are the primary mediators of the rapidupstroke of the action potential of many excitable cell types (e.g.neurons, skeletal myocytes, cardiac myocytes), and thus are critical forthe initiation of signaling in those cells (Hille, Bertil, Ion Channelsof Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland,Mass., 2001)). Because of the role NaV's play in the initiation andpropagation of neuronal signals, antagonists that reduce NaV currentscan prevent or reduce neural signaling. Thus NaV channels are consideredlikely targets in pathologic states where reduced excitability ispredicted to alleviate the clinical symptoms, such as pain, epilepsy,and some cardiac arrhythmias (Chahine, M., Chatelier, A., Babich, O.,and Krupp, J. J., Voltage-gated sodium channels in neurologicaldisorders. CNS Neurol Disord Drug Targets 7 (2), 144 (2008)).

The NaV's form a subfamily of the voltage-gated ion channel super-familyand comprises 9 isoforms, designated NaV 1.1-NaV 1.9. The tissuelocalizations of the nine isoforms vary greatly. NaV 1.4 is the primarysodium channel of skeletal muscle, and NaV 1.5 is primary sodium channelof cardiac myocytes. NaV's 1.7, 1.8 and 1.9 are primarily localized tothe peripheral nervous system, while NaV's 1.1, 1.2, 1.3, and 1.6 areneuronal channels found in both the central and peripheral nervoussystems. The functional behaviors of the nine isoforms are similar butdistinct in the specifics of their voltage-dependent and kineticbehavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G.,International Union of Pharmacology. XLVII. Nomenclature andstructure-function relationships of voltage-gated sodium channels.Pharmacol Rev 57 (4), 397 (2005)).

NaV channels have been identified as the primary target for someclinically useful pharmaceutical agents that reduce pain (Cummins, T.R., Sheets, P. L., and Waxman, S. G., The roles of sodium channels innociception: Implications for mechanisms of pain. Pain 131 (3), 243(2007)). The local anesthetic drugs such as lidocaine block pain byinhibiting NaV channels. These compounds provide excellent local painreduction but suffer the drawback of abolishing normal acute pain andsensory inputs. Systemic administration of these compounds results indose limiting side effects that are generally ascribed to block neuralchannels in the CNS (nausea, sedation, confusion, ataxia). Cardiac sideeffects can also occur, and indeed these compounds are also used asclass 1 anti-arrhythmics, presumably due to block of NaV1.5 channels inthe heart. Other compounds that have proven effective at reducing painhave also been suggested to act by sodium channel blockade includingcarbamazepine, lamotragine, and tricyclic antidepressants (Soderpalm,B., Anticonvulsants: aspects of their mechanisms of action. Eur J Pain 6Suppl A, 3 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block ofpersistent late Na+ currents by antidepressant sertraline andparoxetine. J Membr Biol 222 (2), 79 (2008)). These compounds arelikewise dose limited by adverse effects similar to those seen with thelocal anesthetics. Antagonists that specifically block only theisoform(s) critical for nocioception are expected to have increasedefficacy since the reduction of adverse effects caused by block ofoff-target channels should enable higher dosing and thus more completeblock of target channels isoforms.

Four NaV isoforms, NaV 1.3, 1.7, 1.8, and 1.9, have been specificallyindicated as likely pain targets. NaV 1.3 is normally found in the painsensing neurons of the dorsal root ganglia (DRG) only early indevelopment and is lost soon after birth both in humans and in rodents.Nonetheless, nerve damaging injuries have been found to result in areturn of the NaV 1.3 channels to DRG neurons and this may contribute tothe abnormal pain signaling in various chronic pain conditions resultingfrom nerve damage (neuropathic pain). These data have led to thesuggestion that pharmaceutical block of NaV 1.3 could be an effectivetreatment for neuropathic pain. In opposition to this idea, globalgenetic knockout of NaV 1.3 in mice does not prevent the development ofallodynia in mouse models of neuropathic pain (Nassar, M. A. et al.,Nerve injury induces robust allodynia and ectopic discharges in NaV 1.3null mutant mice. Mol Pain 2, 33 (2006)). It remains unknown whethercompensatory changes in other channels allow for normal neuropathic painin NaV 1.3 knockout mice, though it has been reported that knockout ofNaV 1.1 results in drastic upregulation of NaV 1.3. The converse effectin NaV 1.3 knockouts might explain these results.

NaV 1.7, 1.8, and 1.9 are highly expressed in DRG neurons, including theneurons whose axons make up the C-fibers and Aδ nerve fibers that arebelieved to carry most pain signals from the nocioceptive terminals tothe central nervous system. Like NaV 1.3, NaV 1.7 expression increasesafter nerve injury and may contribute to neuropathic pain states. Thelocalization of NaV 1.7, 1.8, and 1.9 in nocioceptors led to thehypothesis that reducing the sodium currents through these channelsmight alleviate pain. Indeed, specific interventions that reduce thelevels of these channels have proven effective in animal models of pain.

Specific reduction of NaV 1.7 in rodents by multiple differenttechniques has resulted in the reduction of observable pain behaviors inmodel animals. Injection of a viral antisense NaV 1.7 cDNA constructgreatly reduces normal pain responses due to inflammation or mechanicalinjury (Yeomans, D. C. et al., Decrease in inflammatory hyperalgesia byherpes vector-mediated knockdown of NaV 1.7 sodium channels in primaryafferents. Hum Gene Ther 16 (2), 271 (2005)). Likewise, a geneticknockout of NaV 1.7 in a subset of nociceptor neurons reduced acute andinflammatory pain in mouse models (Nassar, M. A. et al.,Nociceptor-specific gene deletion reveals a major role for NaV 1.7 (PN1)in acute and inflammatory pain. Proc Natl Acad Sci USA 101 (34), 12706(2004)). Global knockout of NaV 1.7 in mice leads to death in pupspresumably due to a disruption in olfactory-guided feeding. SelectiveNaV1.7 ablation in both sensory and sympathetic neurons in mice preventsmechanical and thermal hypersensitivity induced by inflammation andnerve injury, and attenuates normal withdrawal responses to noxious heat(Minett, M. S. et al., Distinct Nav1.7-dependent pain sensations requiredifferent sets of sensory and sympathetic neurons. Nat Comm 3, 791(2012)) recapitulating the pain-free phenotype of humans with NaV1.7loss-of function mutations.

Treatments that specifically reduce NaV 1.8 channels in rodent modelseffectively reduce pain sensitivity. Knockdown of NaV 1.8 in rats byintrathecal injection of antisense oligodeoxynucleotides reducesneuropathic pain behaviors, while leaving acute pain sensation intact(Lai, J. et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143(2002); Porreca, F. et al., A comparison of the potential role of thetetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in ratmodels of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640 (1999)).Global genetic knockout of NaV 1.8 in mice or specific destruction ofNaV 1.8 expressing neurons greatly reduces perception of acutemechanical, inflammatory, and visceral pain (Akopian, A. N. et al., Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways. Nat Neurosci 2 (6), 541 (1999); Abrahamsen, B. et al.,The cell and molecular basis of mechanical, cold, and inflammatory pain.Science 321 (5889), 702 (2008); Laird, J. M., Souslova, V., Wood, J. N.,and Cervero, F., Deficits in visceral pain and referred hyperalgesia inNaV 1.8 (SNS/PN3)-null mice. J Neurosci 22 (19), 8352 (2002)). Incontrast to the antisense experiments in rats, genetic knockout miceappear to develop neuropathic pain behaviors normally after nerve injury(Lai, J. et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143(2002); Akopian, A. N. et al., The tetrodotoxin-resistant sodium channelSNS has a specialized function in pain pathways. Nat Neurosci 2 (6), 541(1999); Abrahamsen, B. et al., The cell and molecular basis ofmechanical, cold, and inflammatory pain. Science 321 (5889), 702 (2008);Laird, J. M., Souslova, V., Wood, J. N., and Cervero, F., Deficits invisceral pain and referred hyperalgesia in NaV 1.8 (SNS/PN3)-null mice.J Neurosci 22 (19), 8352 (2002)).

NaV 1.9 global knock out mice have decreased sensitivity to inflammationinduced pain, despite normal acute, and neuropathic pain behaviors(Amaya, F. et al., The voltage-gated sodium channel Na(v)1.9 is aneffector of peripheral inflammatory pain hypersensitivity. J Neurosci 26(50), 12852 (2006); Priest, B. T. et al., Contribution of thetetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensorytransmission and nociceptive behavior. Proc Natl Acad Sci USA 102 (26),9382 (2005)). Spinal knockdown of NaV 1.9 had no apparent effect on painbehavior in rats (Porreca, F. et al., A comparison of the potential roleof the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2,in rat models of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640(1999)).

The understanding of the role of NaV channels in human physiology andpathology has been greatly advanced by the discovery and analysis ofnaturally occurring human mutations. NaV 1.1 and NaV 1.2 mutationsresult in various forms of epilepsy (Fujiwara, T., Clinical spectrum ofmutations in SCN1A gene: severe myoclonic epilepsy in infancy andrelated epilepsies. Epilepsy Res 70 Suppl 1, S223 (2006); George, A. L.,Jr., Inherited disorders of voltage-gated sodium channels. J Clin Invest115 (8), 1990 (2005); Misra, S. N., Kahlig, K. M., and George, A. L.,Jr., Impaired NaV1.2 function and reduced cell surface expression inbenign familial neonatal-infantile seizures. Epilepsia 49 (9), 1535(2008)). Mutations of the NaV 1.4 cause muscular disorders likeparamyotonia congenital (Vicart, S., Sternberg, D., Fontaine, B., andMeola, G., Human skeletal muscle sodium channelopathies. Neurol Sci 26(4), 194 (2005)). NaV 1.5 mutations result in cardiac abnormalities likeBrugada Syndrome and long QT syndrome (Bennett, P. B., Yazawa, K.,Makita, N., and George, A. L., Jr., Molecular mechanism for an inheritedcardiac arrhythmia. Nature 376 (6542), 683 (1995); Darbar, D. et al.,Cardiac sodium channel (SCN5A) variants associated with atrialfibrillation. Circulation 117 (15), 1927 (2008); Wang, Q. et al., SCN5Amutations associated with an inherited cardiac arrhythmia, long QTsyndrome. Cell 80 (5), 805 (1995)).

Recent discoveries have demonstrated that mutations in the gene thatencodes the NaV 1.7 channel (SCN9A) can cause both enhanced and reducedpain syndromes. Work by Waxman's group and others have identified atleast 15 mutations that result in enhanced current through NaV 1.7 andare linked to dominant congenital pain syndromes. Mutations that lowerthe threshold for NaV 1.7 activation cause inherited erythromelalgia(IEM). IEM patients exhibit abnormal burning pain in their extremities.Mutations that interfere with the normal inactivation properties of NaV1.7 lead to prolonged sodium currents and cause paroxysmal extreme paindisorder (PEPD). PEPD patients exhibit periocular, perimandibular, andrectal pain symptoms that progresses throughout life (Drenth, J. P. etal., SCN9A mutations define primary erythermalgia as a neuropathicdisorder of voltage gated sodium channels. J Invest Dermatol 124 (6),1333 (2005); Estacion, M. et al., NaV 1.7 gain-of-function mutations asa continuum: A1632E displays physiological changes associated witherythromelalgia and paroxysmal extreme pain disorder mutations andproduces symptoms of both disorders. J Neurosci 28 (43), 11079 (2008)).

NaV 1.7 null mutations in human patients were recently described byseveral groups (Ahmad, S. et al., A stop codon mutation in SCN9A causeslack of pain sensation. Hum Mol Genet 16 (17), 2114 (2007); Cox, J. J.et al., An SCN9A channelopathy causes congenital inability to experiencepain. Nature 444 (7121), 894 (2006); Goldberg, Y. P. et al.,Loss-of-function mutations in the NaV 1.7 gene underlie congenitalindifference to pain in multiple human populations. Clin Genet 71 (4),311 (2007)). In all cases patients exhibit congenital indifference topain. These patients report no pain under any circumstances. Many ofthese patients suffer dire injuries early in childhood since they do nothave the protective, normal pain that helps to prevent tissue damage anddevelop appropriate protective behaviors. Aside from the striking lossof pain sensation and reduced or absent sense of smell (Goldberg, Y. P.et al., Loss-of-function mutations in the NaV 1.7 gene underliecongenital indifference to pain in multiple human populations. ClinGenet 71 (4), 311 (2007)), these patients appear completely normal.Despite the normally high expression of NaV 1.7 in sympathetic neurons(Toledo-Aral, J. J. et al., Identification of PN1, a predominantvoltage-dependent sodium channel expressed principally in peripheralneurons. Proc Natl Acad Sci USA 94 (4), 1527 (1997)) and adrenalchromatin cells (Klugbauer, N., Lacinova, L., Flockerzi, V., andHofmann, F., Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells. EMBO J 14 (6), 1084 (1995)), these NaV1.7-null patients show no sign of neuroendocrine or sympathetic nervousdysfunction.

The gain of NaV 1.7 function mutations that cause pain, coupled with theloss of NaV 1.7 function mutations that abolish pain, provide strongevidence that NaV 1.7 plays an important role in human pain signaling.The relative good health of NaV 1.7-null patients indicates thatablation of NaV 1.7 is well tolerated in these patients.

Unfortunately, the efficacy of currently used sodium channel blockersfor the disease states described above has been to a large extentlimited by a number of side effects. These side effects include variousCNS disturbances such as blurred vision, dizziness, nausea, and sedationas well more potentially life threatening cardiac arrhythmias andcardiac failure. Accordingly, there remains a need to develop additionalNa channel antagonists, preferably those with higher potency and fewerside effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I:

or a pharmaceutically acceptable salt thereof

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress- or exercise induced angina,palpitations, hypertension, migraine, or abnormal gastro-intestinalmotility.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,

-   wherein, independently for each occurrence:-   ring A is a fused cycloalkyl or heterocycloalkyl ring;-   ring B is a substituted or unsubstituted aryl or heteroaryl ring;-   ring C is a substituted or unsubstituted aryl or heteroaryl ring;-   R¹ is C1-C6 alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl,    fluoro-C1-C6 alkoxy, or oxo;-   R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl,    fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or    (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO,    CF₂, or NR⁷;-   R³ is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or    fluoro-C1-C6 alkoxy;-   n, o, and p are integers from 0 to 4 inclusive;-   R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and-   R⁸ is H, CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl,    heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention can optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. The phrase “optionally substituted” isused interchangeably with the phrase “substituted or unsubstituted.” Asdescribed herein, the variables in formula I encompass specific groups,such as, for example, alkyl or cycloalkyl. Unless otherwise noted, eachof the specific groups for the variables can be optionally substitutedwith one or more substituents of halo, cyano, oxoalkoxy, hydroxy, amino,nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can beoptionally substituted with one or more of halo, cyano, oxoalkoxy,hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additionalexample, an aryl group can be optionally substituted with one or more ofhalo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. As one ofordinary skill in the art will recognize, combinations of substituentsenvisioned by this invention are those combinations that result in theformation of stable or chemically feasible compounds. The term “stable”,as used herein, refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production, detection,and preferably their recovery, purification, and use for one or more ofthe purposes disclosed herein. In some embodiments, a stable compound orchemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week. When twoalkoxy groups are bound to the same atom or adjacent atoms, the twoalkoxy groups can form a ring together with the atom(s) to which theyare bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3.

The term “aliphatic”, “aliphatic group” or “alkyl” as used herein, meansa straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups. The term “cycloaliphatic” or “cycloalkyl” meana monocyclic hydrocarbon, bicyclic, or tricyclic hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic and has a single point of attachment to therest of the molecule. In some embodiments, “cycloaliphatic” refers to amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, “heterocycloalkyl” or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic, or tricyclic ringsystems in which one or more ring atoms in one or more ring members isan independently selected heteroatom. Heterocyclic ring can be saturatedor can contain one or more unsaturated bonds. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”,“heterocycloalkyl” or “heterocyclic” group has three to fourteen ringatoms in which one or more ring atoms is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring atoms.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN,N-di-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “arylkyl,” “aralkoxy,” “arylkoxy,” or “aryloxyalkyl”, refersto monocyclic, bicyclic, and tricyclic ring systems having a total offive to fourteen ring carbon atoms, wherein at least one ring in thesystem is aromatic and wherein each ring in the system contains 3 to 7ring carbon atoms. The term “aryl” may be used interchangeably with theterm “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringatoms, wherein at least one ring in the system is aromatic, at least onering in the system contains one or more heteroatoms, and wherein eachring in the system contains 3 to 7 ring atoms. The term “heteroaryl” maybe used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and cis and trans conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. Thus, included withinthe scope of the invention are tautomers of compounds of formula I.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds of formulaI, wherein one or more hydrogen atoms are replaced with deuterium ortritium, or one or more carbon atoms are replaced by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools, probes inbiological assays, or sodium channel blockers with an improvedtherapeutic profile.

In one embodiment, the invention features compounds of formula I whereinring A is a fused cycloalkyl ring, ring B is an aryl ring and ring C isa substituted or unsubstituted aryl; R¹ is C1-C6 alkyl, C1-C6 alkoxy,halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, or oxo; R² is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy,N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up totwo CH₂ units may be replaced with O, CO, CF₂, or NR⁷; R³ is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or fluoro-C1-C6alkoxy; n, o, and p are integers from 0 to 4 inclusive; R⁷ is H, C1-C6alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃, CO₂R⁷, OH,aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷,CON(R⁷)₂, CN, or SO₂R⁷. In another embodiment, R¹ is C1-C6 alkyl, halo,or oxo. In yet another embodiment, R¹ is CH₃, F, or oxo. In anotherembodiment, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo,CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O,CO, CF₂, or NR⁷. More specifically, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN,OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, R³ is C1-C6 alkyl.In a further embodiment, R³ is CH₃.

In some embodiments, ring A is

In other embodiments, ring B is

In one embodiment, ring C is

wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷.

In a further embodiment, two occurrences of R⁴ and R⁵, or R⁵ and R⁶together with the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.

In a further embodiment, R⁴ is H, C1-C6 alkoxy, or halo. R⁴ may also beH, OCH₃, or F. In one embodiment, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy,halo, CN, OH, or fluoro-C1-C6 alkyl. In another embodiment, R⁵ is H,CH₃, OCH₃, F, Cl, CN, OH, or CF₃. In certain embodiments, R⁶ is H, C1-C6alkoxy, fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain,branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷. In someembodiments, R⁶ is H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH,OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH, OCH₂CH₂OtBu,CH₂C(CHO₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂, OCH₂CF₃,OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃, OCH₂CH₂OCH₂CF₃,OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃, OCH(CH₃)CH₂CF₃,OCH₂CF₂CHF₂,

In one embodiment, R⁴ and R⁵ together with the carbons to which they areattached may also form an optionally substituted ring comprising up to 2heteroatoms.

In another embodiment, ring C is

In further embodiments, R⁵ and R⁶ together with the carbons to whichthey are attached form an optionally substituted ring comprising up to 2heteroatoms.

In one embodiment, ring C is

In another embodiment, the invention features compounds of formula Iwherein ring A is a fused cycloalkyl ring, ring B is an aryl ring andring C is a substituted or unsubstituted heteroaryl; R¹ is C1-C6 alkyl,C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, or oxo; R²is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or (C1-C8)-R⁸ whereinup to two CH₂ units may be replaced with O, CO, CF₂, or NR⁷; R³ is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or fluoro-C1-C6alkoxy; n, o, and p are integers from 0 to 4 inclusive; R⁷ is H, C1-C6alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃, CO₂R⁷, OH,aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷,CON(R⁷)₂, CN, or SO₂R⁷. In another embodiment, R¹ is C1-C6 alkyl, halo,or oxo. In yet another embodiment, R¹ is CH₃, F, or oxo. In anotherembodiment, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo,CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O,CO, CF₂, or NR⁷. More specifically, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN,OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, R³ is C1-C6 alkyl.In a further embodiment, R³ is CH₃. In some embodiments, ring A is

In other embodiments, ring B is

In some embodiments, ring C is a pyridyl or quinoline ring. In a furtherembodiment, ring C is selected from:

In another embodiment, the invention features compounds of formula Iwherein ring A is a fused cycloalkyl ring, ring B is a heteroaryl ringand ring C is a substituted or unsubstituted aryl; R¹ is C1-C6 alkyl,C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, or oxo; R²is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or (C1-C8)-R⁸ whereinup to two CH₂ units may be replaced with O, CO, CF₂, or NR⁷; R³ is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or fluoro-C1-C6alkoxy; n, o, and p are integers from 0 to 4 inclusive; R⁷ is H, C1-C6alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃, CO₂R⁷, OH,aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷,CON(R⁷)₂, CN, or SO₂R⁷. In another embodiment, R¹ is C1-C6 alkyl, halo,or oxo. In yet another embodiment, R¹ is CH₃, F, or oxo. In anotherembodiment, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo,CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O,CO, CF₂, or NR⁷. More specifically, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN,OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, R³ is C1-C6 alkyl.In further embodiment, R³ is CH₃. In some embodiments, ring A is

In one embodiment, ring B is a pyridyl, thiazole, pyrimidine, pyrazole,furan, thiophene, pyrrole, oxazole, imidazole, isoxazole, isothiazole,pyridazine, or pyrazine ring. In another embodiment, ring B is

In one embodiment, ring C is

wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷.

In a further embodiment, two occurrences of R⁴ and R⁵, or R⁵ and R⁶together with the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.

In a further embodiment, R⁴ is H, C1-C6 alkoxy, or halo. R⁴ may also beH, OCH₃, or F. In one embodiment, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy,halo, CN, OH, or fluoro-C1-C6 alkyl. In another embodiment, R⁵ is H,CH₃, OCH₃, F, Cl, CN, OH, or CF₃. In certain embodiments, R⁶ is H, C1-C6alkoxy, fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain,branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷. In someembodiments, R⁶ is H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH,OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH, OCH₂CH₂OtBu,CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂, OCH₂CF₃,OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃, OCH₂CH₂OCH₂CF₃,OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃, OCH(CH₃)CH₂CF₃,OCH₂CF₂CHF₂,

In one embodiment, R⁴ and R⁵ together with the carbons to which they areattached may also form an optionally substituted ring comprising up to 2heteroatoms.

In another embodiment, ring C is

In further embodiments, R⁵ and R⁶ together with the carbons to whichthey are attached form an optionally substituted ring comprising up to 2heteroatoms. In one embodiment, ring C is

In another embodiment, the invention features compounds of formula Iwherein ring A is a fused heterocycloalkyl ring, ring B is an aryl ringand ring C is a substituted or unsubstituted aryl; R¹ is C1-C6 alkyl,C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, or oxo; R²is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or (C1-C8)-R⁸ whereinup to two CH₂ units may be replaced with O, CO, CF₂, or NR⁷; R³ is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, or fluoro-C1-C6alkoxy; n, o, and p are integers from 0 to 4 inclusive; R⁷ is H, C1-C6alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃, CO₂R⁷, OH,aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷,CON(R⁷)₂, CN, or SO₂R⁷. In another embodiment, R¹ is C1-C6 alkyl, halo,or oxo. In yet another embodiment, R¹ is CH₃, F, or oxo. In anotherembodiment, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo,CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O,CO, CF₂, or NR⁷. More specifically, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN,OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, R³ is C1-C6 alkyl.In further embodiment, R³ is CH₃.

In some embodiments, ring A is

In some embodiments, ring B is

In one embodiment, ring C is

wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷.

In a further embodiment, two occurrences of R⁴ and R⁵, or R⁵ and R⁶together with the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.

In a further embodiment, R⁴ is H, C1-C6 alkoxy, or halo. R⁴ may also beH, OCH₃, or F. In one embodiment, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy,halo, CN, OH, or fluoro-C1-C6 alkyl. In another embodiment, R⁵ is H,CH₃, OCH₃, F, Cl, CN, OH, or CF₃. In certain embodiments, R⁶ is H, C1-C6alkoxy, fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain,branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷. In someembodiments, R⁶ is H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH,OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH, OCH₂CH₂OtBu,CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂, OCH₂CF₃,OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃, OCH₂CH₂OCH₂CF₃,OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃, OCH(CH₃)CH₂CF₃,OCH₂CF₂CHF₂,

In another embodiment, R⁴ and R⁵ together with the carbons to which theyare attached may also form an optionally substituted ring comprising upto 2 heteroatoms.

In another embodiment, ring C is

In further embodiments, R⁵ and R⁶ together with the carbons to whichthey are attached form an optionally substituted ring comprising up to 2heteroatoms.

In one embodiment, ring C is

In another embodiment, the invention features compounds of formula Iwherein ring A is a fused heterocycloalkyl ring, ring B is an aryl ringand ring C is a substituted or unsubstituted heteroaryl; R¹ is C1-C6alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, oroxo; R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl,fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or(C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO, CF₂,or NR⁷; R³ is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl,or fluoro-C1-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive;R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃,CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂,NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷. In another embodiment, R¹ is C1-C6alkyl, halo, or oxo. In yet another embodiment, R¹ is CH₃, F, or oxo. Inanother embodiment, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl,halo, CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced withO, CO, CF₂, or NR⁷. More specifically, R² is CH₃, OCH₃, CF₃, F, Cl, Br,CN, OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, R³ is C1-C6alkyl. In further embodiment, R³ is CH₃. In some embodiments, ring A is

In some embodiments, ring B is

In some embodiments, ring C is a pyridyl, pyrazolopiperidine, orquinolone ring. In a further embodiment, ring C is selected from:

In another embodiment, the invention features compounds of formula Iwherein ring A is a fused heterocycloalkyl ring, ring B is a heteroarylring and ring C is a substituted or unsubstituted aryl; R¹ is C1-C6alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, oroxo; R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl,fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or(C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO, CF₂,or NR⁷; R³ is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl,or fluoro-C1-C6 alkoxy; n, o, and p are integers from 0 to 4 inclusive;R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃,CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂,NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷. In another embodiment, R¹ is C1-C6alkyl, halo, or oxo. In yet another embodiment, R¹ is CH₃, F, or oxo. Inanother embodiment, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl,halo, CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced withO, CO, CF₂, or NR⁷. More specifically, R² is CH₃, OCH₃, CF₃, F, Cl, Br,CN, OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, R³ is C1-C6alkyl. In further embodiment, R³ is CH₃. In some embodiments, ring A is

In one embodiment, ring B is a pyridyl, thiazole, pyrimidine, pyrazole,furan, thiophene, pyrrole, oxazole, imidazole, isoxazole, isothiazole,pyridazine, or pyrazine ring. In another embodiment, ring B is

In one embodiment, ring C is

wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷.

In a further embodiment, two occurrences of R⁴ and R⁵, or R⁵ and R⁶together with the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.

In a further embodiment, R⁴ is H, C1-C6 alkoxy, or halo. R⁴ may also beH, OCH₃, or F. In one embodiment, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy,halo, CN, OH, or fluoro-C1-C6 alkyl. In another embodiment, R⁵ is H,CH₃, OCH₃, F, Cl, CN, OH, or CF₃. In certain embodiments, R⁶ is H, C1-C6alkoxy, fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain,branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷. In someembodiments, R⁶ is H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH,OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH, OCH₂CH₂OtBu,CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂, OCH₂CF₃,OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃, OCH₂CH₂OCH₂CF₃,OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃, OCH(CH₃)CH₂CF₃,OCH₂CF₂CHF₂,

In one embodiment, R⁴ and R⁵ together with the carbons to which they areattached may also form an optionally substituted ring comprising up to 2heteroatoms.

In another embodiment, ring C is

In further embodiments, R⁵ and R⁶ together with the carbons to whichthey are attached form an optionally substituted ring comprising up to 2heteroatoms. In one embodiment, ring C is

In one embodiment, the compound has formula IA:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, ring B is an aryl or heteroaryl ring; R² is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy,N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up totwo CH₂ units may be replaced with O, CO, CF₂, or NR⁷; o is an integerfrom 0 to 4 inclusive; R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH,OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, orfluoro-C1-C6 alkoxy; R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷,NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂,heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, orcyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to three CH₂ units maybe replaced with O, CO, S, SO, SO₂, or NR⁷; R⁷ is H, C1-C6 alkyl, CHF₂,CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃, CO₂R⁷, OH, aryl, heteroaryl,C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, orSO₂R⁷.

In some embodiments, ring B is an aryl ring. In one embodiment, R² isC1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo, CN, or (C1-C8)-R⁸wherein up to two CH₂ units may be replaced with O, CO, CF₂, or NR⁷. Inanother embodiment, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN, OCH₂CH₂OtBu,OCH₂CH(CH₃)₂. In a further embodiment, ring B is a phenyl ring.

In certain embodiments, ring B is

In certain embodiments, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN,OH, or fluoro-C1-C6 alkyl. In others, R⁵ is H, CH₃, OCH₃, F, Cl, CN, OH,or CF₃. Yet in others, R⁶ is H, C1-C6 alkoxy, fluoro-C1-C6 alkoxy,SO₂R⁷, SO₂N(R⁷)₂, or a straight chain, branched, or cyclic (C1-C8)-R⁸ orfluoro-(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O,CO, S, SO, SO₂, or NR⁷. R⁶ may also be H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂,C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH,OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂,OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃,OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃,OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,

In one embodiment,

of compound of formula IA is selected from:

In some embodiments, ring B is a heteroaryl ring. In one embodiment, R²is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo, CN, or(C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO, CF₂,or NR⁷. In another embodiment, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN,OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In a further embodiment, ring B is a pyridyl,thiazole, pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole,imidazole, isoxazole, isothiazole, pyridazine, or pyrazine ring. In someembodiments, ring B is

In certain embodiments, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN,OH, or fluoro-C1-C6 alkyl. In others, R⁵ is H, CH₃, OCH₃, F, Cl, CN, OH,or CF₃. Yet in others, R⁶ is H, C1-C6 alkoxy, fluoro-C1-C6 alkoxy,SO₂R⁷, SO₂N(R⁷)₂, or a straight chain, branched, or cyclic (C1-C8)-R⁸ orfluoro-(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O,CO, S, SO, SO₂, or NR⁷. R⁶ may also be H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂,C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH,OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂,OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃,OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃,OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,

In certain embodiments, the compound has formula IB:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN,fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷,SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replacedwith O, CO, CF₂, or NR⁷; o is an integer from 0 to 4 inclusive; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷; R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl and R⁸ is H,CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl,N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷. In further embodiments, R² isC1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo, CN, or (C1-C8)-R⁸wherein up to two CH₂ units may be replaced with O, CO, CF₂, or NR⁷.Alternatively, R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN, OCH₂CH₂OtBu,OCH₂CH(CH₃)₂. R² may also be F, Cl, or CN. In some embodiments, o is 0,1 or 2. In others, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, orfluoro-C1-C6 alkyl. In some embodiments, R⁵ is H, CH₃, OCH₃, F, Cl, CN,OH, or CF₃. In certain embodiments, R⁶ is H, C1-C6 alkoxy, fluoro-C1-C6alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain, branched, or cyclic(C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to three CH₂ units may bereplaced with O, CO, S, SO, SO₂, or NR⁷. In others, R⁶ is H, OCH₂CH₂CF₃,OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃,C(CH₃)₂OH, OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH,OCH₂CF₂CHF₂, OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃,OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃,OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,

In some embodiments,

is selected from:

In some embodiments, the compound has formula IC:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN,fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷,SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replacedwith O, CO, CF₂, or NR⁷; o is an integer from 0 to 4 inclusive; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷; R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H,CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl,N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷.

In some embodiments, R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6alkyl, halo, CN, or (C1-C8)-R⁸ wherein up to two CH₂ units may bereplaced with 0, CO, CF₂, or NR⁷. In others, R² is CH₃, OCH₃, CF₃, F,Cl, Br, CN, OCH₂CH₂OtBu, OCH₂CH(CH₃)₂. In some embodiments, o is 0, 1,or 2. In further embodiments, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo,CN, OH, or fluoro-C1-C6 alkyl. Alternatively, R⁵ is H, CH₃, OCH₃, F, Cl,CN, OH, or CF₃. In some further embodiments, R⁶ is H, C1-C6 alkoxy,fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain, branched, orcyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to three CH₂ units maybe replaced with O, CO, S, SO, SO₂, or NR⁷. In others, R⁶ is H,OCH₂CH₂CF₃, OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃,CH₂OCH₂CH₂CF₃, C(CH₃)₂OH, OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂,OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂, OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂,SO₂CHF₂, OCH₂CF₂CH₃, OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃,OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃, OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,

In one embodiment,

is selected from:

In one embodiment, the compound is selected from Table 1:

Table 1.

TABLE 1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

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25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

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43

44

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47

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49

50

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52

53

54

55

56

57

58

59

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71

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83

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95

96

97

98

99

100

101

102

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104

105

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108

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110

111

112

113

114

115

116

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118

119

120

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135

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140

141

142

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150

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153

154

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159

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176

177

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190

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192

193

194

195

196

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198

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211

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278

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296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

In another embodiment, the compound may exist as a racemic mixture ofenantiomers according to Table 2:

Table 2.

TABLE 2

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

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541

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614

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619

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621

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623

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626

627

628

In another aspect, the invention features a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium ion channel in:

-   -   a patient; or    -   a biological sample;        comprising administering to the patient, or contacting the        biological sample, with a compound or composition of the        invention. In another embodiment, the voltage-gated sodium ion        channel is NaV 1.7.

In another aspect, the invention features a method of treating orlessening the severity of the pain in a subject afflicted with acute,chronic, neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress- or exercise induced angina,palpitations, hypertension, migraine, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound orcomposition of the invention.

In another embodiment, the method is used for treating or lessening theseverity of the pain in a subject afflicted with femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; neuropathic low back pain;myofascial pain syndrome; fibromyalgia; temporomandibular joint pain;chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic andacute headache pain; migraine; tension headache, including, clusterheadaches; chronic and acute neuropathic pain, post-herpatic neuralgia;diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, abdominal pain; pyelonephritis; appendicitis;cholecystitis; intestinal obstruction; hernias; chest pain, cardiacpain; pelvic pain, renal colic pain, acute obstetric pain, labor pain;cesarean section pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, endometriosis; acute herpes zoster pain; sickle cellanemia; acute pancreatitis; breakthrough pain; orofacial pain includingsinusitis pain, dental pain; multiple sclerosis (MS) pain; pain indepression; leprosy pain; Behcet's disease pain; adiposis dolorosa;phlebitic pain; Guillain-Barre pain; painful legs and moving toes;Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladderand urogenital disease, including, urinary incontinence; hyperactivitybladder; painful bladder syndrome; interstitial cyctitis (IC);prostatitis; complex regional pain syndrome (CRPS), type I and type II;widespread pain, paroxysmal extreme pain, pruritis, tinnitis, orangina-induced pain.

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Scheme 1 through Scheme 15 aremethods for preparing the compounds of the invention.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the invention provides compounds that are inhibitorsof voltage-gated sodium ion channels, and thus the present compounds areuseful for the treatment of diseases, disorders, and conditionsincluding, but not limited to acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence. Accordingly, in another aspect of theinvention, pharmaceutically acceptable compositions are provided,wherein these compositions comprise any of the compounds as describedherein, and optionally comprise a pharmaceutically acceptable carrier,adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method of treatment or lessening the severityof stroke, cerebral ischemia, traumatic brain injury, amyotrophiclateral sclerosis, stress- or exercise induced angina, palpitations,hypertension, migraine, or abnormal gastro-intestinal motility isprovided comprising administering an effective amount of a compound, ora pharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain isprovided comprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof. Incertain other embodiments, a method for the treatment or lessening theseverity of radicular pain, sciatica, back pain, head pain, or neck painis provided comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof. In still other embodiments, a method for the treatment orlessening the severity of severe or intractable pain, acute pain,postsurgical pain, back pain, tinnitis or cancer pain is providedcomprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,including, abdominal; pancreatic; IBS pain; chronic and acute headachepain; migraine; tension headache, including, cluster headaches; chronicand acute neuropathic pain, including, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac Pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); or prostatitis; complexregional pain syndrome (CRPS), type I and type II; angina-induced painis provided, comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof.

In certain embodiments of the invention an “effective amount” of thecompound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the subject to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the invention will be decided by the attending physicianwithin the scope of sound medical judgment. The specific effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the subject; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “subject” or “patient”, as used herein, means an animal, preferablya mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,or NaV1.9, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation or hyperactivity of one or more of NaV 1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where activation orhyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.7 and/or NaV1.8.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such asNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

-   -   (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,        oxymorphone, levorphanol, levallorphan, methadone, meperidine,        fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,        hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine or        pentazocine;    -   (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,        diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,        flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,        ketorolac, meclofenamic acid, mefenamic acid, meloxicam,        nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,        oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,        tolmetin or zomepirac;    -   (3) a barbiturate sedative, e.g. amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal or thiopental;    -   (4) a benzodiazepine having a sedative action, e.g.        chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,        oxazepam, temazepam or triazolam;    -   (5) a histamine antagonist of the H₁ receptor having a sedative        action, e.g. diphenhydramine, pyrilamine, promethazine,        chlorpheniramine or chlorocyclizine;    -   (6) a sedative such as glutethimide, meprobamate, methaqualone        or dichloralphenazone;    -   (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,        chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;    -   (8) an NMDA receptor antagonist, e.g. dextromethorphan        ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan        ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,        pyrroloquinoline quinine,        cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,        EN-3231 (MorphiDex®), a combination formulation of morphine and        dextromethorphan), topiramate, neramexane or perzinfotel        including an NR2B antagonist, e.g. ifenprodil, traxoprodil or        (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;    -   (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, or        4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)        quinazoline;    -   (10) a tricyclic antidepressant, e.g. desipramine, imipramine,        amitriptyline or nortriptyline;    -   (11) an anticonvulsant, e.g. carbamazepine, lamotrigine,        topiratmate or valproate;    -   (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or        NK-I antagonist, e.g.        ([alpha]R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine        (2S,3S);    -   (13) a muscarinic antagonist, e.g. oxybutynin, tolterodine,        propiverine, tropsium chloride, darifenacin, solifenacin,        temiverine and ipratropium;    -   (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;    -   (15) a coal-tar analgesic, in particular paracetamol;    -   (16) a neuroleptic such as droperidol, chlorpromazine,        haloperidol, perphenazine, thioridazine, mesoridazine,        trifluoperazine, fluphenazine, clozapine, olanzapine,        risperidone, ziprasidone, quetiapine, sertindole, aripiprazole,        sonepiprazole, blonanserin, iloperidone, perospirone,        raclopride, zotepine, bifeprunox, asenapine, lurasidone,        amisulpride, balaperidone, palindore, eplivanserin, osanetant,        rimonabant, meclinertant, Miraxion® or sarizotan;    -   (17) a vanilloid receptor agonist (e.g. resiniferatoxin) or        antagonist (e.g. capsazepine);    -   (18) a beta-adrenergic such as propranolol;    -   (19) a local anaesthetic such as mexiletine;    -   (20) a corticosteroid such as dexamethasone;    -   (21) a 5-HT receptor agonist or antagonist, particularly a 5-HTi        B/I D agonist such as eletriptan, sumatriptan, naratriptan,        zolmitriptan or rizatriptan;    -   (22) a 5-HT2A receptor antagonist such as        R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol        (MDL-100907);    -   (23) a cholinergic (nicotinic) analgesic, such as ispronicline        (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine        (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine        (ABT-594) or nicotine;    -   (24) Tramadol®;    -   (25) a PDEV inhibitor, such as        5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (sildenafil),        (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione        (IC-351 or tadalafil),        2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        (vardenafil),        5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,        3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;        an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methyl        gabapentin,        (1[α],3[α],5[α])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic        acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (2S,4S)-4-(3-chlorophenoxy)proline,        (2S,4S)-4-(3-fluorobenzyl)-proline,        [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,        3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,        C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,        (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,        (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,        (3S,5R)-3-amino-5-methyl-nonanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and        (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;    -   (26) a cannabinoid;    -   (27) metabotropic glutamate subtype 1 receptor (mGluR1)        antagonist;    -   (28) a serotonin reuptake inhibitor such as sertraline,        sertraline metabolite demethylsertraline, fluoxetine,        norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine,        paroxetine, citalopram, citalopram metabolite        desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine,        ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone,        cericlamine and trazodone;    -   (29) a noradrenaline (norepinephrine) reuptake inhibitor, such        as maprotiline, lofepramine, mirtazepine, oxaprotiline,        fezolamine, tomoxetine, mianserin, buproprion, buproprion        metabolite hydroxybuproprion, nomifensine and viloxazine        (Vivalan®), especially a selective noradrenaline reuptake        inhibitor such as reboxetine, in particular (S,S)-reboxetine;    -   (30) a dual serotonin-noradrenaline reuptake inhibitor, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   (31) an inducible nitric oxide synthase (iNOS) inhibitor such as        S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,        S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,        S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,        (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic        acid,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,        (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3        pyridinecarbonitrile,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,        N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,        or guanidinoethyldisulfide;    -   (32) an acetylcholinesterase inhibitor such as donepezil;    -   (33) a prostaglandin E2 subtype 4 (EP4) antagonist such as        7V-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide        or        4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic        acid;    -   (34) a leukotriene B4 antagonist; such as        1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic        acid (CP-105696),        5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric        acid (ONO-4057) or DPC-11870,    -   (35) a 5-lipoxygenase inhibitor, such as zileuton,        6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone        (ZD-2138), or        2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);        (36) a sodium channel blocker, such as lidocaine;    -   (36) a 5-HT3 antagonist, such as ondansetron; and the        pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the additional therapeutic agent is an NaV 1.8inhibitor. NaV 1.7 and NaV 1.8 ion channels are both highly expressed inthe sensory neurons of the dorsal root ganglion, where pain signalsoriginate, but the distinct functional behavior of the two channelsleads them to fulfill distinct and complementary roles in neuronalexcitability. Na_(V)1.7 controls the general sensitivity of nociceptiveneurons, and initiating the painful signal in a nociceptor. Na_(V)1.8amplifies and sustains the pain signal once it has been initiated.Because of these distinct roles, inhibiting both channels shouldincrease the effectiveness of pain relief. Preclinical genetic knockoutmice support this idea, as double knockouts of Na_(V)1.7 and Na_(V)1.8channels in the sensory DRG neurons surprisingly diminish nociceptivebehaviors to a greater degree than knockout of either channel alone.

In another embodiment, the additional appropriate therapeutic agent isan NaV 1.8 inhibitor selected from the following:2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)benzamide;2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-4-(trifluoromethyl)benzamide;2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-(2-methoxyethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4-(trifluoromethyl)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-4-(trifluoromethyl)benzamide;4-chloro-2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(2-fluoro-6-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(2-chloro-6-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-cyano-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-cyano-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-cyanophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide;2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluoromethyl)benzamide;2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluoromethoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethoxy)benzamide;2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(2-fluoro-6-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluoromethoxy)benzamide;2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)benzamide;2-(4-ethoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-ethoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-methoxy-4-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-fluoro-6-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-chloro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-chloro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-chloro-2-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(5-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)-5-(trifluoromethyl)benzamide;2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(5-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(3-fluoro-5-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(6-chloro-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-propoxyphenoxy)-5-(trifluoromethyl)benzamide;2-(4-methoxy-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-isopropoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-chloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-chloro-2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-chloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide;2-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide;2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-fluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide;2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,3,4-trifluorophenoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,3,5-trimethylphenoxy)benzamide;2-(2,3-difluoro-4-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,4,5-trimethylphenoxy)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2,3,5-trimethylphenoxy)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxybenzamide;2-(4-cyclopropylphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(4-(tert-butoxy)phenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(4-ethoxyphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-fluoro-2-(4-isopropylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide;5-fluoro-2-(4-(2-methoxyethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(2-chloro-4-methoxyphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-fluoro-2-(4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2,4,5-trimethylphenoxy)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(2,2,2-trifluoroethoxy)phenoxy)benzamide;2-(4-(cyclopropylmethoxy)phenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(2-chloro-3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide;4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide;2-(isopentyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-((2R)-bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-((1-methylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((tetrahydrofuran-3-yl)methoxy)-4-(trifluoromethyl)benzamide;2-cyclobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-4-(trifluoromethyl)benzamide;2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-((1R,5S)-bicyclo[3.1.0]hexan-3-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-((2,2-difluorocyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;4-chloro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)benzamide;2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5-(trifluoromethyl)benzamide;2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)-2-(3,3,3-trifluoropropoxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5-(trifluoromethoxy)benzamide;2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;4-(tert-butyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;4-(tert-butyl)-N-(6-oxo-1,6-dihydropyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;4-chloro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;N-(6-oxo-1,6-dihydropyridin-3-yl)-4-(trifluoromethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;2-((6-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;4-(tert-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;4-(tert-butyl)-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide;2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide;2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide;2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide;2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide;2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide;2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide;N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4,6-bis(trifluoromethyl)benzamide;2-(4-fluoro-2-(hydroxymethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide;5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(4,4,4-trifluorobutoxy)phenoxy)benzamide,or combinations thereof.

In another embodiment, the additional appropriate therapeutic agent isan NaV 1.8 inhibitor selected from the following:3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide;3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(2-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-phenoxy-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide;N-(3-sulfamoylphenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(3-(N-methylsulfamoyl)phenyl)quinoxaline-2-carboxamide;4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoicacid; 5-(3-(4-fluorophenoxy)quinoxaline-2-carboxamido)picolinic acid;5-(3-(4-fluoro-2-methylphenoxy)quinoxaline-2-carboxamido)picolinic acid;5-(3-phenoxyquinoxaline-2-carboxamido)picolinic acid;5-(3-(2-fluoro-4-methoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(4-(2,2,2-trifluoroethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(4-chloro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(2-(difluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid; 5-(3-(4-chloro-2-methylphenoxy)quinoxaline-2-carboxamido)picolinicacid; 5-(3-(2,4-dimethoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(3-fluoro-4-methoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid; 5-(3-(2-chloro-4-fluorophenoxy)quinoxaline-2-carboxamido)picolinicacid; 5-(3-(2,4-difluorophenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(2-chloro-4-methoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid;5-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid;44344-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid;4-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinicacid;3-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)quinoxaline-2-carboxamide;3-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)benzoic acid;2-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)thiazole-4-carboxylicacid;3-(4-fluoro-2-methoxyphenoxy)-N-(1H-1,2,4-triazol-3-yl)quinoxaline-2-carboxamide;2-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)oxazole-4-carboxylicacid;3-(4-fluoro-2-methoxyphenoxy)-N-(1H-pyrazol-3-yl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(1H-tetrazol-5-yl)quinoxaline-2-carboxamide;N-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(1H-pyrazol-4-yl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(2-(hydroxymethyl)-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide;N-(3-(1H-tetrazol-5-yl)phenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(1H-indazol-6-yl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(1H-indazol-5-yl)quinoxaline-2-carboxamide;N-(1H-benzo[d]imidazol-6-yl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;N-(4-cyanopyridin-2-yl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;N-(6-cyanopyridin-3-yl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;N-(5-cyanopyridin-2-yl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-3-yl)quinoxaline-2-carboxamide;N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide;N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;N-(3-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide;2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-phenoxy-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;N-(3-sulfamoylphenyl)-2-(4-(2,2,2-trifluoroethoxy)phenoxy)quinoline-3-carboxamide;N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide;2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;dimethoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;2-(2-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide;4-(2-(2,4-difluorophenoxy)quinoline-3-carboxamido)benzoic acid;4-(2-(4-fluoro-2-methylphenoxy)quinoline-3-carboxamido)benzoic acid;4-(2-(2-(difluoromethoxy)phenoxy)quinoline-3-carboxamido)benzoic acid;4-(2-(2,4-dimethoxyphenoxy)quinoline-3-carboxamido)benzoic acid;5-(2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxamido)picolinic acid;5-(2-(2,4-difluorophenoxy)quinoline-3-carboxamido)picolinic acid, orcombinations thereof.

In another embodiment, the additional appropriate therapeutic agent isan NaV 1.8 inhibitor selected from the following:4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoicacid; 4-(2-(2,4-difluorophenoxy)-4-(perfluoroethyl)benzamido)benzoicacid;4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid;4-(2-(2-chloro-4-fluorophenoxy)-4-(trifluoromethyl)benzamido)benzoicacid;4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoicacid; 4-(2-(2,4-difluorophenoxy)-4-(trifluoromethyl)benzamido)benzoicacid;4-(2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)benzoicacid;4-(2-(2,4-difluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoicacid;4-(2-(4-fluoro-2-methylphenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoicacid;4-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoicacid; 4-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoicacid; 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoicacid; 4-(4,5-dichloro-2-(4-fluorophenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-phenoxybenzamido)benzoic acid;4-(4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(4-(2,2,2-trifluoroethoxy)phenoxy)benzamido)benzoicacid; 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoicacid; 4-(4,5-dichloro-2-(2-(difluoromethoxy)phenoxy)benzamido)benzoicacid; 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoicacid; 4-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)benzamido)benzoic acid;4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid;4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid;4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoicacid;4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoicacid; 5-(4,5-dichloro-2-(4-fluorophenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(4-(isopentyloxy)phenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-phenoxybenzamido)picolinic acid;5-(4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(4-(2,2,2-trifluoroethoxy)phenoxy)benzamido)picolinicacid; 5-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)picolinicacid; 5-(4,5-dichloro-2-(2-(difluoromethoxy)phenoxy)benzamido)picolinicacid; 5-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)picolinicacid; 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)benzamido)picolinic acid;5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid;5-(2-(2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-fluoro-2-methylphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid;5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid; 5-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid; 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid; 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid; 5-(4-(tert-butyl)-2-(4-fluoro-2-methylphenoxy)benzamido)picolinicacid; 5-(4-(tert-butyl)-2-(4-fluorophenoxy)benzamido)picolinic acid;5-(2-(4-fluorophenoxy)benzamido)picolinic acid;5-(2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamido)picolinic acid;5-(2-(4-fluoro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(2-chloro-4-fluorophenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(5-fluoro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(2-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-chloro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid; 5-(2-(2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid; 5-(2-(2-chlorophenoxy)-5-(trifluoromethyl)benzamido)picolinicacid; 5-(2-(2-isopropoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid; 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-chloro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-methoxy-2-methylphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(2-chloro-4-methoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid;5-(2-(3-fluoro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid; 5-(2-phenoxy-5-(trifluoromethyl)benzamido)picolinic acid;5-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)picolinic acid;5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinicacid; 5-(2-(4-fluorophenoxy)-4-(perfluoroethyl)benzamido)picolinic acid;5-(2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamido)picolinicacid;5-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)picolinicacid; 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid, or combinations thereof.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, activity in a biological sample or a subject, which methodcomprises administering to the subject, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to, thestudy of sodium ion channels in biological and pathological phenomena;and the comparative evaluation of new sodium ion channel inhibitors.

Examples General Methods

¹H NMR (400 MHz or 300 MHz) and ¹³C NMR (100 MHz) spectra were obtainedas solutions in deuterioacetonitrile (CD₃CN), chloroform-d (CDCl₃),deuteromethanol (MeOD-d4), or dimethyl sulfoxide-D₆ (DMSO). Mass spectra(MS) were obtained using an Applied Biosystems API EX LC/MS systemequipped with a Phenomenex 50×4.60 mm luna-5μ, C18 column. The LC/MSeluting system was 1-99% or 10-99% acetonitrile in H₂O with 0.035% v/vtrifluoroacetic acid, 0.035% v/v formic acid, 5 mM HCl or 5 mM ammoniumformate using a 3 or 15 min linear gradient and a flow rate of 12mL/min. Silica gel chromatography was performed using silica gel-60 witha particle size of 230-400 mesh. Pyridine, DCM (CH₂Cl₂), tetrahydrofuran(THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and1,4-dioxane were from Aldrich Sure-Seal bottles kept under dry nitrogen.All reactions were stirred magnetically unless otherwise noted.

[(3aR,7aR)-7a-phenyl-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanoneStep 1: tert-butyl 4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylate

A solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(10.0 g, 32.3 mmol) and bromobenzene (5.1 g, 3.4 mL, 32.3 mmol) in DMF(30 mL), was treated with sodium carbonate (16.2 mL of 2 M, 32.3 mmol)in water. The reaction mixture was purged with nitrogen and treated withPd(dppf)Cl₂ (1.2 g, 1.6 mmol). The reaction mixture was stirred at 80°C. for 1 h. Volatiles were removed under reduced pressure at 70° C. Theremaining residue was partitioned between ethyl acetate (100 mL) andwater (100 mL). The mixture was filtered to remove emulsifying solids.The organic layer was further washed with saturated aqueous NaCl, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting brown oil was purified by silica gel columnchromatography: 120 gram silica gel column, 0-40% ethyl acetate/hexanegradient over 30 min to afford tert-butyl4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylate (8.13 g, mmol, 97%) as aclear colorless oil. ESI-MS m/z calc. 259.2. found 260.3 (M+1)⁺;Retention time: 2.05 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Aryl Halide Product 1-bromo-3,5- tert-butyl 4-(3,5-difluorophenyl)-3,6-difluoro-benzene dihydro-2H-pyridine-1-carboxylate 1-Bromo-3-fluoro-tert-butyl 4-(3-fluorophenyl)-3,6-dihydro- benzene2H-pyridine-1-carboxylate 1-bromo-4-fluoro- tert-butyl4-(4-fluorophenyl)-3,6-dihydro- benzene 2H-pyridine-1-carboxylate 2,6-tert-butyl 4-(6-bromo-2-pyridyl)-3,6-dihydro- Dibromopyridine2H-pyridine-1-carboxylate 2-bromo-1,4- tert-butyl4-(2,5-difluorophenyl)-3,6-dihydro- difluoro-benzene2H-pyridine-1-carboxylate 2-bromo-3-chloro- tert-butyl4-(3-chloro-2-pyridyl)-3,6-dihydro- pyridine 2H-pyridine-1-carboxylate2-bromo-3-methoxy- tert-butyl 4-(3-methoxy-1-oxido-pyridin-1-1-oxido-pyridin- ium-2-yl)-3,6-dihydro-2H-pyridine-1- 1-ium carboxylate2-bromopyrimidine tert-butyl 4-pyrimidin-2-yl-3,6-dihydro-2H-pyridine-1-carboxylate 2-chloro-3- tert-butyl4-(3-fluoro-2-pyridyl)-3,6-dihydro- fluoro-pyridine2H-pyridine-1-carboxylate 3-bromo-1- tert-butyl4-(1-methylpyrazol-3-yl)-3,6- methyl-pyrazoledihydro-2H-pyridine-1-carboxylate 3-bromobenzonitrile tert-butyl4-(3-cyanophenyl)-3,6-dihydro-2H- pyridine-1-carboxylate 4-bromo-2-tert-butyl 4-(2-methylthiazol-4-yl)-3,6- methyl-thiazoledihydro-2H-pyridine-1-carboxylate 4-bromothiazole tert-butyl4-thiazol-4-yl-3,6-dihydro-2H- pyridine-1-carboxylate bromobenzenetert-butyl 4-phenyl-3,6-dihydro-2H-pyridine- 1-carboxylate 1-bromo-3-tert-butyl 4-(3-chlorophenyl)-3,6-dihydro-2H- chloro-benzenepyridine-1-carboxylate 1-bromo-2,3- tert-butyl4-(2,3-difluorophenyl)-5,6- difluoro-benzenedihydropyridine-1(2H)-carboxylate 2-bromo-1,4- tert-butyl4-(2,5-difluorophenyl)-3,6-dihydro- difluoro-benzene2H-pyridine-1-carboxylate 2-bromo-6-(trifluoro- tert-butyl6-(trifluoromethyl)-5′,6′-dihydro- methyl)pyridine[2,4′-bipyridine]-1′(2′H)-carboxylate 2-bromo-4-(trifluoro- tert-butyl4-[4-(trifluoromethyl)-2-pyridyl]- methyl)pyridine3,6-dihydro-2H-pyridine-1-carboxylate 2,6-dichloro- tert-butyl4-(6-chloro-4-methoxy-2-pyridyl)- 4-methoxy-pyridine3,6-dihydro-2H-pyridine-1-carboxylate 2,6-dibromopyridine tert-butyl6-bromo-5′,6′-dihydro-[2,4′- bipyridine]-1′(2′H)-carboxylate

Step 2:tert-butyl(3R,4R)-3,4-dihydroxy-4-phenyl-piperidine-1-carboxylate

Methanesulfonamide (917 mg, 9.6 mmol) was dissolved in a solution ofwater (54 mL) and tert-butanol (54 mL). AD-mix-β (7.6 g, 9.6 mmol) wasadded, and the mixture was allowed to stir at rt for 5 min beforecooling to 0° C. To the mixture was added tert-butyl4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylate (2.5 g, 9.6 mmol) in oneportion, and the reaction mixture was allowed to continue stirring at 0°C. for 8 h. Sodium sulfite (6 g) was added, and the mixture was allowedto stir at rt for an additional 30 min and was extracted with ethylacetate (2×75 mL). The combined organic layers were washed with aqueous1 N NaOH (1×75 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to a yellow-orange oil. It was purified by silicagel column chromatography: 40 gram silica gel column, 0-30% ethylacetate/hexane gradient over 30 min; product eluted at 25% to providetert-butyl(3R,4R)-3,4-dihydroxy-4-phenyl-piperidine-1-carboxylate (1.6g, 58%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (dt, J=3.1, 1.8Hz, 2H), 7.44-7.35 (m, 2H), 7.33-7.27 (m, 1H), 4.26-4.12 (m, 1H),4.11-4.01 (m, 1H), 3.95 (d, J=11.7 Hz, 1H), 3.22-3.08 (m, 1H), 3.07-2.93(m, 1H), 2.71 (s, 1H), 1.96-1.79 (m, 2H), 1.64 (t, J=18.5 Hz, 1H),1.55-1.44 (m, 9H). ESI-MS m/z calc. 293.2. found 294.5 (M+1)⁺; Retentiontime: 1.32 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor tert-butyl (3R,4R)-3,4-dihydroxy-4-(3,5- tert-butyl4-(3,5-difluorophenyl)-3,6- difluorophenyl)-pyridine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-tert-butyl 4-(3-fluorophenyl)-3,6-fluorophenyl)-piperidine-1-carboxylate dihydro-2H-pyridine-1-carboxylatetert-butyl (3R,4R)-3,4-dihydroxy-4-(4- tert-butyl4-(4-fluorophenyl)-3,6- fluorophenyl)-piperidine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl(3R,4R)-3,4-dihydroxy-(6-bromo- tert-butyl 4-(6-bromo-2-pyridyl)-3,6-2-pyridyl)-piperidine-1-carboxylate dihydro-2H-pyridine-1-carboxylatetert-butyl (3R,4R)-3,4-dihydroxy-4-(2,5- tert-butyl4-(2,5-difluorophenyl)-3,6- difluorophenyl)-piperidine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-tert-butyl 4-(3-chloro-2-pyridyl)-3,6-chloro-2-pyridyl)-piperidine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-tert-butyl 4-(3-methoxy-1-oxido-pyridin-methoxy-1-oxido-pyridin-1-ium-2-yl)-1-ium-2-yl)-3,6-dihydro-2H-pyridine-1- piperidine-1-carboxylatecarboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4- tert-butyl4-pyrimidin-2-yl-3,6-dihydro- pyrimidin-2-yl-piperidine-1-carboxylate2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-tert-butyl 4-(3-fluoro-2-pyridyl)-3,6-fluoro-2-pyridyl)-piperidine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(1-tert-butyl 4-(1-methylpyrazol-3-yl)-3,6-methylpyrazol-3-yl)-piperidine-1- dihydro-2H-pyridine-1-carboxylatecarboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(3- tert-butyl4-(3-cyanophenyl)-3,6-dihydro- cyanophenyl)-piperidine-1-carboxylate2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(2-tert-butyl 4-(2-methylthiazol-4-yl)-3,6-methylthiazol-4-yl)-piperidine-1- dihydro-2H-pyridine-1-carboxylatecarboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-thiazol- tert-butyl4-thiazol-4-yl-3,6-dihydro-2H- 4-yl-piperidine-1-carboxylatepyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-phenyl-tert-butyl 4-phenyl-3,6-dihydro-2H- piperidine-1-carboxylatepyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-4-(3- tert-butyl4-(3-chlorophenyl)-3,6- chlorophenyl)-piperidine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl(3R,4R)-3,4-dihydroxy-4-(2,3- tert-butyl 4-(2,3-difluorophenyl)-5,6-difluorophenyl)-piperidine-1-carboxylatedihydropyridine-1(2H)-carboxylate tert-butyl(3R,4R)-3,4-dihydroxy-4-(2,5- tert-butyl 4-(2,5-difluorophenyl)-3,6-difluorophenyl)-piperidine-1-carboxylatedihydro-2H-pyridine-1-carboxylate tert-butyl (3R,4R)-3,4-dihydroxy-6-tert-butyl 6-(trifluoromethyl)-5′,6′-(trifluoromethyl)-piperidine-1-carboxylatedihydro-[2,4′-bipyridine]-1′(2′H)- carboxylate tert-butyl(3R,4R)-3,4-dihydroxy-4-[4- tert-butyl 4-[4-(trifluoromethyl)-2-(trifluoromethyl)-2-pyridy1]-piperidine-1-pyridyl]-3,6-dihydro-2H-pyridine-1- carboxylate carboxylate tert-butyl(3R,4R)-3,4-dihydroxy-4-(6- tert-butyl 4-(6-chloro-4-methoxy-2-chloro-4-methoxy-2-pyridyl)-piperidine-1-pyridyl)-3,6-dihydro-2H-pyridine-1- carboxylate carboxylate tert-butyl(3R,4R)-4-(6-bromopyridin-2-yl)- tert-butyl 6-bromo-5′,6′-dihydro-[2,4′-3,4-dihydroxypiperidine-1-carboxylate bipyridine]-1′(2′H)-carboxylate

Step 3:tert-butyl(3aR,7aR)-7a-phenyl-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate

In a 100 mL flask equipped with a nitrogen inlet,tert-butyl(3R,4R)-3,4-dihydroxy-4-phenyl-piperidine-1-carboxylate (1.3g, 4.5 mmol) was dissolved in DMF (7 mL). The solution was cooled to 0°C. before the addition of sodium hydride (395 mg, 9.86 mmol) (60 wt %dispersion in mineral oil). The reaction mixture was allowed to stir at0° C. for 20 min before the addition of dibromomethane (344 μL, 4.94mmol). Following addition, the 0° C. ice bath was removed, and thereaction mixture was allowed to stir at rt for 20 h. Water and saturatedaqueous NaCl (total volume of 50 mL) were added and the product wasextracted with ethyl acetate (2×30 mL). The organic layers werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The obtained oil (1.76 grams) was dissolved in DCM andpurified by silica gel column chromatography (80 g column): 0-10% ethylacetate/hexane gradient over 25 min, then 10-40% over 15 min. The purefractions were combined and concentrated to providetert-butyl(3aR,7aR)-7a-phenyl-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(1.0 g, 73%) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃) δ7.42-7.34 (m, 4H), 7.33-7.25 (m, 1H), 5.25 (s, 1H), 4.84 (s, 1H), 4.29(s, 1H), 3.95 (d, J=13.0 Hz, 1H), 3.59-3.50 (m, 2H), 3.43 (td, J=12.3,3.9 Hz, 1H), 2.15-1.91 (m, 2H), 1.50 (s, 9H). ESI-MS m/z calc. 305.2.found 306.0 (M+1)⁺; Retention time: 1.74 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor tert-butyl (3aR,7aR)-7a-(3,5- tert-butyl(3R,4R)-3,4-dihydroxy-4-(3,5- difluorophenyl)-3a,4,6,7-tetrahydro-difluorophenyl)-pyridine-1-carboxylate[1,3]dioxolo[4,5-c]pyridine-5-carboxylate tert-butyl(3aR,7aR)-7a-(3-fluorophenyl)- tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-fluorophenyl)-piperidine-1-carboxylate c]pyridine-5-carboxylatetert-butyl (3aR,7aR)-7a-(4-fluorophenyl)- tert-butyl(3R,4R)-3,4-dihydroxy-4-(4- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-fluorophenyl)-piperidine-1-carboxylate c]pyridine-5-carboxylatetert-butyl (3aR,7aR)-7a-(6-bromo-2- tert-butyl (3R,4R)-3,4-dihydroxy-(6-pyridyl)-3a,4,6,7-tetrahydro- bromo-2-pyridyl)-piperidine-1-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate carboxylate tert-butyl(3aR,7aR)-7a-(2,5- tert-butyl (3R,4R)-3,4-dihydroxy-4-(2,5-difluorophenyl)-3a,4,6,7-tetrahydro-difluorophenyl)-piperidine-1-carboxylate[1,3]dioxolo[4,5-c]pyridine-5-carboxylate tert-butyl(3aR,7aR)-7a-(3-chloro-2- tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-pyridyl)-3a,4,6,7-tetrahydro- chloro-2-pyridyl)-piperidine-1-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate carboxylate tert-butyl(3aR,7aR)-7a-(3-methoxy-1- tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-oxido-pyridin-1-ium-2-yl)-3a,4,6,7- methoxy-1-oxido-pyridin-1-ium-2-yl)-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5- piperidine-1-carboxylatecarboxylate tert-butyl (3aR,7aR)-7a-4-pyrimidin-2-yl- tert-butyl(3R,4R)-3,4-dihydroxy-4- piperidine-3a,4,6,7-tetrahydro-pyrimidin-2-yl-piperidine-1-carboxylate[1,3]dioxolo[4,5-c]pyridine-5-carboxylate tert-butyl(3aR,7aR)-7a-(3-fluoro-2- tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-pyridyl)-piperidine-3a,4,6,7-tetrahydro-fluoro-2-pyridyl)-piperidine-1-carboxylate[1,3]dioxolo[4,5-c]pyridine-5-carboxylate tert-butyl(3aR,7aR)-7a-(1-methylpyrazol- tert-butyl (3R,4R)-3,4-dihydroxy-4-(1-3-yl)-piperidine-3a,4,6,7-tetrahydro- methylpyrazol-3-yl)-piperidine-1-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate carboxylate tert-butyl(3aR,7aR)-7a-(3-cyanophenyl)- tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-cyanophenyl)-piperidine-1-carboxylate c]pyridine-5-carboxylatetert-butyl (3aR,7aR)-7a-(2-methylthiazol- tert-butyl(3R,4R)-3,4-dihydroxy-4-(2- 4-yl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-methylthiazol-4-yl)-piperidine-1- c]pyridine-5-carboxylate carboxylatetert-butyl (3aR,7aR)-7a-thiazol-4-yl- tert-butyl(3R,4R)-3,4-dihydroxy-4- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-thiazol-4-yl-piperidine-1-carboxylate c]pyridine-5-carboxylatetert-butyl (3aR,7aR)-7a-phenyl-3a,4,6,7- tert-butyl(3R,4R)-3,4-dihydroxy-4- tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-phenyl-piperidine-1-carboxylate carboxylate tert-butyl(3aR,7aR)-7a-(3-chlorophenyl)- tert-butyl (3R,4R)-3,4-dihydroxy-4-(3-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-chlorophenyl)-piperidine-1-carboxylate c]pyridine-5-carboxylatetert-butyl (3aR,7aR)-7a-(2,3- tert-butyl (3R,4R)-3,4-dihydroxy-4-(2,3-difluorophenyl)-3a,4,6,7-tetrahydro-difluorophenyl)-piperidine-1-carboxylate[1,3]dioxolo[4,5-c]pyridine-5-carboxylate tert-butyl (3aR,7aR)-7a-(2,5-tert-butyl (3R,4R)-3,4-dihydroxy-4-(2,5-difluorophenyl)-3a,4,6,7-tetrahydro-difluorophenyl)-piperidine-1-carboxylate[1,3]dioxolo[4,5-c]pyridine-5-carboxylate tert-butyl(3aR,7aR)-7a-(trifluoromethyl)- tert-butyl (3R,4R)-3,4-dihydroxy-6-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-(trifluoromethyl)-piperidine-1-carboxylate c]pyridine-5-carboxylatetert-butyl (3aR,7aR)-7a--[4- tert-butyl (3R,4R)-3,4-dihydroxy-4-[4-(trifluoromethyl)-2-pyridyl]-3a,4,6,7-(trifluoromethyl)-2-pyridyl]-piperidine-1-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5- carboxylate carboxylatetert-butyl (3aR,7aR)-7a-(6-chloro-4- tert-butyl(3R,4R)-3,4-dihydroxy-4-(6- methoxy-2-pyridyl)-3a,4,6,7-tetrahydro-chloro-4-methoxy-2-pyridyl)-piperidine-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate 1-carboxylate(3aR,7aR)-tert-butyl 7a-(6-bromopyridin- tert-butyl(3R,4R)-4-(6-bromopyridin-2- 2-yl)tetrahydro-[1,3]dioxolo[4,5-yl)-3,4-dihydroxypiperidine-1-carboxylate c]pyridine-5(6H)-carboxylate

Step 4:(3aR,7aR)-7a-phenyl-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine

A solution oftert-butyl(3aR,7aR)-7a-phenyl-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(980 mg, 3.2 mmol) in DCM (8 mL) was treated with 2,2,2-trifluoroaceticacid (2.5 mL). The reaction mixture was stirred at rt for 1.5 h. Thereaction mixture was diluted with DCM (40 mL) and quenched by theaddition of aqueous 1 N NaOH (50 mL). The organic layer was separated,dried over sodium sulfate, filtered and concentrated under reducedpressure to afford(3aR,7aR)-7a-phenyl-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine(608 mg, 93.2%) as a pale brown oil that solidified upon standing. ¹HNMR (400 MHz, CDCl₃) δ 7.45 (dt, J=3.0, 1.8 Hz, 2H), 7.42-7.33 (m, 2H),7.33-7.27 (m, 1H), 5.28 (d, J=0.9 Hz, 1H), 5.05 (d, J=0.8 Hz, 1H), 4.20(dd, J=5.7, 4.8 Hz, 1H), 3.16 (dd, J=13.4, 4.6 Hz, 1H), 3.07-2.94 (m,2H), 2.83 (dt, J=12.6, 5.3 Hz, 1H), 2.15-1.90 (m, 2H), 1.78 (s, 1H).ESI-MS m/z calc. 205.1. found 206.4 (M+1)⁺; Retention time: 0.45 min (3min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor (3aR,7aR)-7a-(3,5-difluorophenyl)- tert-butyl(3aR,7aR)-7a-(3,5- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-difluorophenyl)-3a,4,6,7-tetrahydro- c]pyridine[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- tert-butyl(3aR,7aR)-7a-(3-fluorophenyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate(3aR,7aR)-7a-(4-fluorophenyl)-3a,4,6,7- tert-butyl(3aR,7aR)-7a-(4-fluorophenyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate(3aR,7aR)-7a-(6-bromo-2-pyridyl)- tert-butyl (3aR,7aR)-7a-(6-bromo-2-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- pyridyl)-3a,4,6,7-tetrahydro-c]pyridine [1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(2,5-difluorophenyl)- tert-butyl (3aR,7aR)-7a-(2,5-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-difluorophenyl)-3a,4,6,7-tetrahydro- c]pyridine[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(3-chloro-2-pyridyl)- tert-butyl (3aR,7aR)-7a-(3-chloro-2-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- pyridyl)-3a,4,6,7-tetrahydro-c]pyridine [1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(3-methoxy-1-oxido- tert-butyl (3aR,7aR)-7a-(3-methoxy-1-pyridin-1-ium-2-yl)-3a,4,6,7-tetrahydro-oxido-pyridin-1-ium-2-yl)-3a,4,6,7- [1,3]dioxolo[4,5-c]pyridinetetrahydro-[1,3]dioxolo[4,5-c]pyridine-5- carboxylate(3aR,7aR)-7a-4-pyrimidin-2-yl- tert-butyl (3aR,7aR)-7a-4-pyrimidin-2-yl-piperidine-3a,4,6,7-tetrahydro- piperidine-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine [1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(3-fluoro-2-pyridyl)- tert-butyl (3aR,7aR)-7a-(3-fluoro-2-piperidine-3a,4,6,7-tetrahydro- pyridyl)-piperidine-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine [1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(1-methylpyrazol-3-yl)- tert-butyl(3aR,7aR)-7a-(1-methylpyrazol- piperidine-3a,4,6,7-tetrahydro-3-yl)-piperidine-3a,4,6,7-tetrahydro- [1,3]dioxolo[4,5-c]pyridine[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(3-cyanophenyl)-3a,4,6,7- tert-butyl(3aR,7aR)-7a-(3-cyanophenyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate(3aR,7aR)-7a-(2-methylthiazol-4-yl)- tert-butyl(3aR,7aR)-7a-(2-methylthiazol-4- 3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-yl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridinec]pyridine-5-carboxylate (3aR,7aR)-7a-thiazol-4-yl-3a,4,6,7- tert-butyl(3aR,7aR)-7a-thiazol-4-yl- tetrahydro-[1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate(3aR,7aR)-7a-phenyl-4,5,6,7-tetrahydro- tert-butyl(3aR,7aR)-7a-phenyl-3a,4,6,7- 3aH-[1,3]dioxolo[4,5-c]pyridinetetrahydro-[1,3]dioxolo[4,5-c]pyridine-5- carboxylate(3aR,7aR)-7a-(3-chlorophenyl)-3a,4,6,7- tert-butyl(3aR,7aR)-7a-(3-chlorophenyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate(3aR,7aR)-7a-(2,3-difluorophenyl)- tert-butyl (3aR,7aR)-7a-(2,3-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-difluorophenyl)-3a,4,6,7-tetrahydro- c]pyridine[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(2,5-difluorophenyl)- tert-butyl (3aR,7aR)-7a-(2,5-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-difluorophenyl)-3a,4,6,7-tetrahydro- c]pyridine[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(trifluoromethyl)-3a,4,6,7- tert-butyl(3aR,7aR)-7a-(trifluoromethyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate(3aR,7aR)-7a--[4-(trifluoromethyl)-2- tert-butyl (3aR,7aR)-7a--[4-pyridyl]-3a,4,6,7-tetrahydro- (trifluoromethyl)-2-pyridyl]-3a,4,6,7-[1,3]dioxolo[4,5-c]pyridine tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate (3aR,7aR)-7a-(6-chloro-4-methoxy-2- tert-butyl(3aR,7aR)-7a-(6-chloro-4- pyridyl)-3a,4,6,7-tetrahydro-methoxy-2-pyridyl)-3a,4,6,7-tetrahydro- [1,3]dioxolo[4,5-c]pyridine[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(3aR,7aR)-7a-(pyridin-2-yl)hexahydro- tert-butyl(3aR,7aR)-7a-(pyridin-2-yl)- [1,3]dioxolo[4,5-c]pyridine3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5- c]pyridine-5-carboxylate

6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane Step 1:6-phenyl-3-azabicyclo[4.1.0]heptane

4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (2.1 g, 11.6 mmol wasdissolved in DMF (15 mL), and DIPEA (1.5 g, 2.0 mL, 11.6 mmol) wasadded. A solution of benzylbromide (2.0 g, 1.4 mL, 11.6 mmol) in DMF (5mL) was added dropwise. After 5 min of stirring at rt, the solvent wasremoved under reduced pressure. The remaining oil was dissolved in ethylacetate (75 mL) and washed with saturated aqueous NaCl (1×75 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography: 40 gram silica gel column, 0-15% methanol/DCMgradient over 30 min with 1% aqueous ammonium hydroxide to afford1-benzyl-4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine (3.1 g, 100%) wasobtained as a brownish-red oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.31 (m,6H), 7.27 (ddd, J=7.5, 4.0, 1.7 Hz, 1H), 7.03-6.94 (m, 2H), 6.00 (dt,J=5.0, 1.7 Hz, 1H), 3.64 (s, 2H), 3.16 (dd, J=6.0, 2.9 Hz, 2H), 2.71 (t,J=5.7 Hz, 2H), 2.58-2.48 (m, 2H). ESI-MS m/z calc. 267.1. found 268.4(M+1)⁺; Retention time: 1.09 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor 1-benzyl-4-phenyl-3,6-dihydro- 4-phenyl-1,2,3,6-2H-pyridine tetrahydropyridine 1-benzyl-4-(4-fluorophenyl)-3,6-4-(4-fluorophenyl)-1,2,3,6- dihydro-2H-pyridine tetrahydropyridine

Step 2: 3-benzyl-6-phenyl-3-azabicyclo[4.1.0]heptane

A solution of diethylzinc (39.7 mL of 15% w/v, 48.1 mmol) in toluene wasadded to anhydrous DCM (25 mL) at 0° C. TFA (3.7 mL, 48.1 mmol) in DCM(12 mL) was added, and the resulting slightly gelatinous mixture wasallowed to stir for 20 min at 0° C. Diiodomethane (4.1 mL, 50.5 mmol) inDCM (12 mL) was slowly added dropwise and the reaction mixture wasstirred at 0° C. for 20 min forming white slurry. A solution of1-benzyl-4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine (3.2 g, 12.0 mmol)in DCM (12 mL) was added at 0° C., and the reaction mixture was allowedto stir at rt for 45 min. The reaction mixture was carefully quenchedwith the addition of saturated aqueous ammonium chloride solution (125mL). The organic layer was then washed with 1 N HCl (1×100 mL) andsaturated aqueous sodium bicarbonate solution (1×100 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The remaining oil was purified by silica gel columnchromatography: 40 gram silica gel column, 0-30% ethyl acetate/DCMgradient over 25 min; product eluted at 10% while the quaternaryside-product eluted at 25%. Pure fractions were combined andconcentrated to provide3-benzyl-6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane (1.5 g, 44%) asan orange oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.29 (m, 4H), 7.27-7.19(m, 3H), 6.98-6.90 (m, 2H), 3.54-3.41 (m, 2H), 2.85-2.71 (m, 2H),2.34-2.18 (m, 2H), 2.09 (tdd, J=13.5, 9.0, 6.6 Hz, 2H), 1.34 (dtd,J=8.9, 5.6, 2.0 Hz, 1H), 0.92 (dt, J=9.1, 4.1 Hz, 2H). ESI-MS m/z calc.281.2. found 282.5 (M+1)⁺; Retention time: 1.13 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor 3-benzyl-6-phenyl-3- 1-benzyl-4-phenyl-3,6-dihydro-azabicyclo[4.1.0]heptane 2H-pyridine 3-benzyl-(4-fluorophenyl)-3-1-benzyl-4-(4-fluorophenyl)-3,6- azabicyclo[4.1.0]heptanedihydro-2H-pyridine

Step 3: 6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane

A solution of 1-chloroethyl chloroformate (3.8 g, 2.8 mL, 26.3 mmol) inDCM (3 mL) at 0° C. was treated dropwise with a solution of3-benzyl-6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane (1.5 g, 5.3 mmol)in DCM (6 mL). The reaction mixture was allowed to stir at rt for 30min. Methanol (25 mL) was added to the solution, and it was stirred at40° C. for 30 min. The volatiles were removed under reduced pressure,and the remaining solid was suspended in aqueous 1 N HCl (75 mL). Thesuspension was extracted with ethyl acetate (1×75 mL). The aqueous layerwas adjusted to pH 12 with the addition of aqueous 1 N NaOH (100 mL).The resulting cloudy white suspension was extracted with ethyl acetate(2×75 mL). The final organic layers were combined, dried over sodiumsulfate, filtered and concentrated under reduced pressure to provide6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane (0.8 g, 79%) as a clearyellow oil that crystallized upon standing. ¹H NMR (400 MHz, CDCl₃) δ7.26-7.19 (m, 2H), 6.99-6.91 (m, 2H), 3.36 (dd, J=12.8, 5.7 Hz, 1H),3.08 (d, J=12.7 Hz, 1H), 2.75-2.58 (m, 2H), 2.02 (ddd, J=12.8, 6.3, 4.2Hz, 1H), 1.96-1.86 (m, 1H), 1.42-1.20 (m, 2H), 0.95 (dd, J=9.3, 4.4 Hz,1H), 0.81 (dd, J=5.5, 4.8 Hz, 1H). ESI-MS m/z calc. 191.1. found 192.4(M+1)⁺; Retention time: 0.58 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor 6-(4-fluorophenyl)-3- 3-benzyl-6-phenyl-3-azabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptane 6-phenyl-3-3-benzyl-(4-fluorophenyl)-3- azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptane 2-[(2S,4S)-2-methyl-4- (2S,4S)-tert-butyl4-methoxy-2-tri- (trideuteriomethoxy)-4- deutero-methyl-4-(thiazol-2-piperidyl]thiazole yl)piperidine-1-carboxylate

(4-isopropoxy-3-methylphenyl)(6-phenyl-7-oxa-3-azabicyclo[4.2.0]octan-3-yl)-methanoneStep 1: tert-butyl3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-oxo-piperidine-1-carboxylate

To a solution of O1-tert-butyl O3-ethyl4-oxopiperidine-1,3-dicarboxylate (5 g, 18.4 mmol) in methanol (50 mL)at 0° C. was added sodium borohydride (1.74 g, 46.1 mmol) portionwiseover 15 min. The reaction mixture was stirred at 0° C. for 30 min andwas concentrated under reduced pressure. The resulting residue wasdiluted with water and adjusted to pH 3 with 1N HCl. The mixture wasextracted with ethyl acetate (3×) and the combined organic layers weredried over sodium sulfate and concentrated under reduced pressure toafford tert-butyl 4-hydroxy-3-(hydroxymethyl)piperidine-1-carboxylate(4.1 g) as a white solid.

In a 250 mL round bottom flask containing tert-butyl4-hydroxy-3-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 8.6 mmol)was added dichloromethane (50.0 mL) followed by triethylamine (2.8 mL,20 mmol). tert-Butyldimethylsilyl chloride (1.5 g, 10.2 mmol) was addedportionwise and the reaction mixture was allowed to stir at rt ovn. Thereaction mixture was almost complete by 1 cms. The reaction mixture wasquenched with saturated aqueous ammonium chloride and saturated aqueousNaCl and extracted with dichloromethane. The organic layer was separatedand dried over sodium sulfate and then concentrated under reducedpressure. The crude product was used in the next step withoutpurification.

To a 250 mL round bottom flask containing crude tert-butyl3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxy-piperidine-1-carboxylate(2.4 g) was added DCM (24 mL) and sodium bicarbonate (2.0 g, 20.4 mmol).The reaction mixture was cooled to 0° C. for 5 min and Dess-Martinperiodane (3.6 g, 8.5 mmol) was added. The reaction mixture was stirredfor 3 h while warming to rt. The reaction mixture was filtered andconcentrated under reduced pressure to dryness. The crude product waspurified via silica gel chromatography (0-50%) DCM:ethyl acetate toprovide tert-butyl3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-oxo-piperidine-1-carboxylate(1.7 g, 71%) as a clear yellow oil. ESI-MS m/z calc. 343.5. found 344.4(M+1)⁺; Retention time: 2.47 min (3 min run).

Step 2: tert-butyl4-hydroxy-3-(methylsulfonyloxymethyl)-4-phenyl-piperidine-1-carboxylate

To a 100 mL round bottom flask was added tert-butyl3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-oxo-piperidine-1-carboxylate(1.0 g, 2.9 mmol) and THF (9 mL). The mixture was cooled to −78° C. andphenyl magnesium chloride (1.46 ml, 2 M, 2.9 mmol) was added dropwiseand the reaction mixture was allowed to warm to rt over 1 h. Thereaction mixture was quenched with saturated aqueous ammonium chlorideand extracted with ethyl acetate (3×). The organic layers wereseparated, dried over sodium sulfate, and concentrated under reducedpressure to provide tert-butyl3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxy-4-phenyl-piperidine-1-carboxylateas a clear colorless oil which was diluted with THF (9 mL). The mixturewas treated with tetra-n-butylammonium fluoride (4.4 mL of 1 M, 4.4mmol) and the reaction mixture was allowed to stir at rt for 10 min. Thereaction mixture was quenched with water and extracted with ethylacetate (3×). The organic layers were separated, dried over sodiumsulfate, and concentrated under reduced pressure to afford tert-butyl4-hydroxy-3-(hydroxymethyl)-4-phenyl-piperidine-1-carboxylate which wasdissolved in dichloromethane (9 mL) and treated with triethylamine (0.81mL, 5.8 mmol), and methanesulfonyl chloride (0.23 mL, 2.9 mmol). Thereaction mixture was quenched with water and extracted withdichloromethane (3×). The organic layers were dried over sodium sulfateand concentrated under reduced pressure. The crude reaction mixture waspurified via silica gel chromatography 0%-25% ethyl acetate indichloromethane to afford tert-butyl4-hydroxy-3-(methylsulfonyloxymethyl)-4-phenyl-piperidine-1-carboxylate(0.7 g, 63%) as a pale yellow oil. ESI-MS m/z calc. 385.5. found 386.3(M+1)⁺; Retention time: 1.80 min (3 min run).

Step 3: (4-hydroxy-4-phenyl-3-piperidyl)methyl methanesulfonate

To a 100 mL round bottom flask was added, dichloromethane (10 mL), andHCl (0.45 mL of 4 M, 1.83 mmol) and the reaction mixture was allowed tostir at rt for 4 h. The reaction mixture was concentrated under reducedpressure to afford (4-hydroxy-4-phenyl-3-piperidyl)methylmethanesulfonate hydrochloride (596 mg) which used in the next reactionwithout purification. ESI-MS m/z calc. 285.1. found 286.3 (M+1)⁺;Retention time: 0.92 min (3 min run).

Step 4:(4-hydroxy-1-(4-isopropoxy-3-methylbenzoyl)-4-phenylpiperidin-3-yl)methylmethanesulfonate

To a vial was added the 4-isopropoxy-3-methyl-benzoic acid (39 mg, 0.2mmol), HATU (76 mg, 0.2 mmol), DMF (2 mL), and triethylamine (0.7 mL, 5mmol) and the reaction mixture was allowed to stir for 10 min at rt. Asolution of(4-hydroxy-1-(4-isopropoxy-3-methylbenzoyl)-4-phenylpiperidin-3-yl)methylmethanesulfonate (57 mg, 0.2 mmol) dissolved in DMF (1 mL) was added andthe reaction mixture was allowed to stir for 15 min. The reaction wasquenched with saturated aqueous NaCl and extracted with ethyl acetate.The ethyl acetate layer was further rinsed with saturated aqueous NaCl(3×) to remove any DMF. The organic layers were dried over sodiumsulfate, concentrated under reduced pressure, and used in the nextreaction without further purification. ESI-MS m/z calc. 461.6. found462.1 (M+1)⁺; Retention time: 1.93 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Acid Amine (4-hydroxy-1-(4-isopropoxy-3- 4-isopropoxy-3-(4-hydroxy-4-phenyl-3- methylbenzoyl)-4- methyl-benzoic acidpiperidyl)methyl phenylpiperidin-3-yl)methyl methanesulfonatemethanesulfonate (4-hydroxy-1-(5-isopropoxy-6- 5-isopropoxy-6-(4-hydroxy-4-phenyl-3- methyl-pyridine-2-carboxyl)-4- methyl-pyridine-2-piperidyl)methyl phenylpiperidin-3-yl)methyl carboxylic acidmethanesulfonate methanesulfonate (4-hydroxy-1-(3-methoxy-4-(2-3-methoxy-4-(2- (4-hydroxy-4-phenyl-3-(trifluoromethoxy)ethoxy)benzoyl)- (trifluoromethoxy)ethoxy)benzoicpiperidyl)methyl 4-phenylpiperidin-3-yl)methyl acid methanesulfonatemethanesulfonate (4-hydroxy-1-(2-fluoro-2-methyl- 4-(2-fluoro-2-methyl-(4-hydroxy-4-phenyl-3- propoxy)-3-methoxy-benzoyl)-4-propoxy)-3-methoxy- piperidyl)methyl phenylpiperidin-3-yl)methyl benzoicacid methanesulfonate methanesulfonate (4-hydroxy-1-(quinoline-8-quinoline-8-carboxylic (4-hydroxy-4-phenyl-3-carboxyl)-4-phenylpiperidin-3- acid piperidyl)methyl yl)methylmethanesulfonate methanesulfonate (4-hydroxy-1-(3-methoxy-4-3-methoxy-4-[(3R)- (4-hydroxy-4-phenyl-3-[(3R)-tetrahydrofuran-3-yl]oxy- tetrahydrofuran-3- piperidyl)methylbenzoyl)-4-phenylpiperidin-3- yl]oxy-benzoic acid methanesulfonateyl)methyl methanesulfonate

Step 5:(4-isopropoxy-3-methylphenyl)(6-phenyl-7-oxa-3-azabicyclo[4.2.0]octan-3-yl)-methanone

A vial containing the(4-hydroxy-1-(4-isopropoxy-3-methylbenzoyl)-4-phenylpiperidin-3-yl)methylmethanesulfonate (92 mg, 0.2 mmol) in THF (1.5 mL) was treated with NaHin mineral oil (60%, 8 mg, 0.2 mmol). The reaction mixture was stirredat rt for 1 h, filtered and purified by reverse phase HPLC (1-99%)ACN:H₂O with no modifier) to afford(4-isopropoxy-3-methylphenyl)(6-phenyl-7-oxa-3-azabicyclo[4.2.0]octan-3-yl)-methanone(13 mg, 18%). ¹H NMR (400 MHz, MeOD) δ 7.47-7.22 (m, 7H), 6.99 (t, J=9.1Hz, 1H), 4.72-4.54 (m, 2H), 4.46-4.03 (m, 2H), 3.99-3.74 (m, 2H), 3.66(dd, J=25.7, 12.9 Hz, 1H), 3.09 (t, J=15.9 Hz, 1H), 2.57-2.25 (m, 1H),2.21 (d, J=7.8 Hz, 3H), 1.34 (d, J=5.8 Hz, 6H). ESI-MS m/z calc. 365.5.found 366.5 (M+1)⁺; Retention time: 1.95 min (3 min run).

The following compounds were prepared using the procedure reportedabove:

Product Precursor (4-isopropoxy-3-methylphenyl)(6-(4-hydroxy-1-(4-isopropoxy-3- phenyl-7-oxa-3-azabicyclo[4.2.0]methylbenzoyl)-4-phenylpiperidin- octan-3-yl)-methanone 3-yl)methylmethanesulfonate (5-isopropoxy-6-methyl-pyridine-2-(4-hydroxy-1-(5-isopropoxy-6- carboxyl)-(6-phenyl-7-oxa-3-methyl-pyridine-2-carboxyl)-4- azabicyclo[4.2.0]octan-3-yl)-phenylpiperidin-3-yl)methyl methanone methanesulfonate (3-methoxy-4-(2-(4-hydroxy-1-(3-methoxy-4-(2- (trifluoromethoxy)ethoxy)benzoyl)-(trifluoromethoxy)ethoxy)benzoyl)- (6-phenyl-7-oxa-3-azabicyclo[4.2.0]-4-phenylpiperidin-3-yl)methyl octan-3-yl)-methanone methanesulfonate(4-(2-fluoro-2-methyl-propoxy)-3- (4-hydroxy-1-(2-fluoro-2-methyl-methoxy-benzoyl)-(6-phenyl-7-oxa-3- propoxy)-3-methoxy-benzoyl)-4-azabicyclo[4.2.0]octan-3-yl)- phenylpiperidin-3-yl)methyl methanonemethanesulfonate quinoline-8-carboxyl)-(6-phenyl-7-(4-hydroxy-1-(quinoline-8- oxa-3-azabicyclo[4.2.0]octan-carboxyl)-4-phenylpiperidin- 3-yl)-methanone 3-yl)methylmethanesulfonate3-methoxy-4-[(3R)-tetrahydrofuran-3- (4-hydroxy-1-(3-methoxy-4-[(3R)-yl]oxy-benzoyl)-(6-phenyl-7-oxa-3- tetrahydrofuran-3-yl]oxy-benzoyl)-azabicyclo[4.2.0]octan-3-yl)- 4-phenylpiperidin-3-yl)methyl methanonemethanesulfonate

(3aR,7aR)-tert-butyl7a-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate

A solution of tert-butyl (3aR,7aR)-7a-(6-bromo-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(342 mg, 0.88 mmol) was dissolved in absolute ethanol (10 mL) andstirred under nitrogen before the addition of 10% palladium on carbon(473 mg, 0.44 mmol). The reaction mixture was evacuated and put underhydrogen gas (1 atm) for 2 h. The reaction mixture was filtered througha pad of celite, rinsed with DCM, and concentrated under reducedpressure to providetert-butyl(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(266 mg, 99%) as a clear yellow-brown oil. ¹H NMR (400 MHz, CDCl₃) δ8.99 (s, 1H), 8.44 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 5.35 (s, 1H),5.13 (s, 1H), 4.72 (s, 1H), 4.23 (s, 1H), 4.07 (d, J=15.1 Hz, 1H), 3.60(s, 2H), 2.80 (s, 1H), 2.20 (d, J=14.4 Hz, 1H), 1.49 (s, 9H). ESI-MS m/zcalc. 306.2. found 307.5 (M+1)⁺; Retention time: 1.1 min, (3 min run).

[(3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone

In a vial, 2-tert-butoxyethanol (155 mg, 1.31 mmol) was dissolved in DMF(500 μL). NaH (52 mg, 1.31 mmol) (60% oil dispersion) was added in smallportions and the suspension was stirred at rt for 25 min.[(3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone(50 mg, 0.13 mmol) as a solution in DMF (100 μL) was added and thereaction mixture was stirred at 80° C. for 1 h. The reaction mixture wasquenched by the addition of water and the mixture was extracted with DCM(3×). The combined extracts were dried over sodium sulfate and thevolatiles were removed under reduced pressure. The material wasdissolved in DMF (1 mL) and purified by preparative HPLC using HCl as amodifier. Evaporation of the volatiles provided[(3aR,7aR)-7a-[3-(2-tert-butoxyethoxy)-2-pyridyl]-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[4-(2-tert-butoxyethoxy)-3-chloro-phenyl]methanone(38 mg, 46.5%) as a colorless glass. ESI-MS m/z calc. 576.3. found 577.0(M+1)⁺; Retention time: 1.48 min (3 min run).

7a-(pyridin-2-yl)octahydrofuro[3,2-c]pyridine Step 1: benzyl3-allyl-4-oxo-piperidine-1-carboxylate

A mixture of benzyl 4-oxopiperidine-1-carboxylate (14.0 g, 60.0 mmol),prop-2-en-1-ol (3.4 mL, 50 mmol), pyrrolidine-2-carboxylic acid (1.7 g,15.0 mmol) and(5-diphenylphosphinyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane(1.45 g, 2.5 mmol) in DMSO (100 mL) was purged with nitrogen for 5 min.The mixture was treated with 1,3-diallyl-dichloro-dipalladacyclobutane(457 mg, 1.25 mmol) and heated at 75° C. for 72 h. The reaction mixturewas cooled to rt and filtered through celite (ethyl acetate). Thefiltrate was repartitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate (2×). The combined organic layerswere washed with water (3×), dried over MgSO₄, filtered and concentratedto dryness. The crude material was purified by column chromatography(0-10% ethyl acetate-hexanes) to provide benzyl3-allyl-4-oxo-piperidine-1-carboxylate (11.5 g, 84.1%). ESI-MS m/z calc.273.3. found 274.5 (M+1)⁺; Retention time: 1.72 min (3 min run).

Step 2: benzyl6-(2-hydroxyethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl 3-allyl-4-oxo-piperidine-1-carboxylate (6.0 g,22.0 mmol) in toluene (100 mL) was added ethylene glycol (1.4 g, 1.2 mL,22.0 mmol) followed by the addition of 4-methylbenzenesulfonicacid-(water) (0.6 mL, 3.3 mmol). The reaction mixture was equipped witha Dean-Stark trap and heated at reflux overnight. The reaction mixturewas cooled to rt, washed with saturated sodium bicarbonate (2×),saturated aqueous NaCl, dried over MgSO₄, filtered and concentrated todryness. The crude material benzyl6-allyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate was used directlyin next step without further purification.

A solution of benzyl6-allyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (3.2 g, 10.0 mmol)in DCM (30 mL) was cooled to −78° C. Ozone was bubbled through thesolution for 10 min until a light blue color persisted. The bluesolution was then bubbled with nitrogen gas for 10 min to remove theexcess of ozone. MeOH (30 mL) was added followed by the addition ofsodium borohydride (380 mg, 10.0 mmol). The reaction mixture was stirredat rt for 5 min, and was repartitioned between ethyl acetate and water.The aqueous layer was extracted with ethyl acetate (3×). The combinedorganic layers were washed with saturated aqueous NaCl, dried overMgSO₄, filtered, and concentrated to dryness. The crude material waspurified by column chromatography (30-40% ethyl acetate-hexanes) toprovide benzyl6-(2-hydroxyethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (1.7 g,53%). ESI-MS m/z calc. 321.4. found 322.5 (M+1)⁺; Retention time: 1.44min (3 min run).

Step 3: Step 4: benzyl10-(2-chloroethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl10-(2-hydroxyethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (320mg, 1.0 mmol) in chloroform (10 mL) was added thionyl chloride (290 μL,4.0 mmol) followed by the addition of a drop of pyridine and a drop ofDMF. The reaction mixture was heated at reflux for 1 h, concentrated todryness and purified by column chromatography (10-20% ethylacetate-hexanes) to provide benzyl10-(2-chloroethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (140mg, 41%) as a colorless oil. ESI-MS m/z calc. 339.8. found 340.5 (M+1)⁺;Retention time: 1.89 min (3 min run).

Step 4: benzyl7a-(2-pyridyl)-2,3,3a,4,6,7-hexahydrofuro[3,2-c]pyridine-5-carboxylate

To a solution of benzyl10-(2-chloroethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (68 mg,0.2 mmol) in EtOH (2 mL) was added aqueous HCl (1 mL of 1 M, 1.0 mmol).The reaction mixture was heated in a sealed vial at 70° C. for 3 h. Thevolume was reduced to ⅓. The residue was repartitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetate(2×). The combined organic layers were washed with saturated aqueousNaCl, dried over MgSO₄, filtered and concentrated to dryness to affordcrude benzyl 3-(2-chloroethyl)-4-oxo-piperidine-1-carboxylate which wasused directly in next step without further purification.

A solution of 2-bromopyridine (49 mg, 0.31 mmol) in THF (5 mL) wascooled to −78° C. and treated with butyllithium (10 mg, 0.16 mmol) (1Min hexanes) dropwise under an argon atmosphere. The reaction mixture wasstirred at −78° C. for 30 min and crude benzyl3-(2-chloroethyl)-4-oxo-piperidine-1-carboxylate (46 mg, 0.16 mmol) inTHF (1 mL) was added dropwise. The reaction mixture was allowed to warmto rt and stirred over for 72 h. The reaction mixture was quenched withsaturated aqueous ammonium chloride. The aqueous layer was extractedwith ethyl acetate (3×). The combined organic layers were washed withsaturated aqueous NaCl, dried over MgSO₄, filtered and concentrated todryness. The crude material was purified by column chromatography(20-30% ethyl acetate-hexanes) to provided benzyl7a-(2-pyridyl)-2,3,3a,4,6,7-hexahydrofuro[3,2-c]pyridine-5-carboxylate.ESI-MS m/z calc. 338.4. found 339.3 (M+1)⁺; Retention time: 1.28 min (3min run).

Step 5: 7a-(2-pyridyl)-3,3a,4,5,6,7-hexahydro-2H-furo[3,2-c]pyridine

A solution of benzyl7a-(2-pyridyl)-2,3,3a,4,6,7-hexahydrofuro[3,2-c]pyridine-5-carboxylate(22 mg, 0.06 mmol) in MeOH (5 mL) was purged with nitrogen for 5 min.The mixture was treated with 10% palladium on carbon (14 mg, 0.013mmol). The mixture was the evacuated and put under a hydrogen atmosphere(balloon) at rt. The Pd-catalyst was removed via filtration and washedwith MeOH. The solvent was removed under reduced pressure affordingcrude 7a-(2-pyridyl)-3,3a,4,5,6,7-hexahydro-2H-furo[3,2-c]pyridine whichwas used directly in next step without further purification. ESI-MS m/zcalc. 204.3. found 205.3 (M+1)⁺; Retention time: 0.184 min (3 min run).

(3aR,7aR)-7a-(6-methyl-2-pyridyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine

A flask containingtert-butyl(3aR,7aR)-7a-(6-bromo-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(84 mg, 0.22 mmol) in THF (1 mL) was treated with Pd(PPh₃)₄ (126 mg,0.11 mmol). The mixture was purged with nitrogen and trimethylalumane(31 mg, 42 μL, 0.44 mmol) was added. The solution was heated to 70° C.over 16 h. Water (1 ml) was added and mixture was extracted with EtOAc(3×). The organic layers were combined and washed with 1 ml of saturatedaqueous NaCl, dried over sodium sulfate, concentrated, providing thetert-butyl(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylateas a yellow oil which was treated with a 1:1 mixture of TFA/DCM (1 mL).The reaction mixture was allowed to stir for 1 h and was concentratedunder reduced pressure to provide(3aR,7aR)-7a-(6-methyl-2-pyridyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine,which was used in the next step without further purification. ESI-MS m/zcalc. 220.1. found 221.1 (M+1)+; Retention time: 0.228 min (3 min run).

7a-(6-isobutoxy-2-pyridyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine

A solution of 2-methylpropan-1-ol (240 μL, 2.60 mmol) in DMF (1 mL) wastreated with sodium hydride (104 mg, 2.6 mmol)(60% dispersion in mineraloil) at 0° C. The reaction mixture was allowed to stir for 5 min andtert-butyl(3aR,7aR)-7a-(6-bromo-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(100 mg, 0.26 mmol) in DMF (0.5 mL) was added. The reaction mixture wasallowed to stir at rt for 16 h. Water (1 ml) was added and mixture wasextracted with ethyl acetate (3×). The organic layers were combined andwashed with saturated aqueous NaCl, dried over sodium sulfate, andconcentrated to afford crudetert-butyl(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylateas a yellow oil. The crude product was treated with a 1 ml of 1:1mixture TFA/DCM and the reaction mixture was allowed to stir for 1 h.The reaction mixture was concentrated under reduced pressure to afford7a-(6-isobutoxy-2-pyridyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridineas yellow oil (50 mg, 51%). ESI-MS m/z calc. 278.3. found 279.2 (M+1)⁺;Retention time: 0.23 min (3 min run).

(3-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)((syn)-7a-(pyridin-2-yl)hexahydrofuro[3,4-c]pyridin-5(3H)-yl)methanoneStep 1: (syn)-tert-butyl1-oxohexahydrofuro[3,4-c]pyridine-5(3H)-carboxylate

A solution of 3H-furo[3,4-c]pyridin-1-one (3.2 g, 23.7 mmol) in HCl (17mL of 1 M, 17 mmol) and water (17 mL) in a Parr shaker was treated withPtO₂ (700 mg, 3.1 mmol). The mixture was hydrogenated at 55 psiovernight. The catalyst was filtered off and the filtrate wasconcentrated to afford a yellow oil. The resulting oil was diluted withDCM (237 mL) and MeOH (35 mL) and was treated with TEA (8.3 mL, 59.2mmol) followed by Boc-anhydride (5.7 g, 26.1 mmol). The reaction mixturewas stirred at rt for 16 h. The reaction mixture was diluted with waterand extracted with DCM (3×). The combined organics were dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Purification by flashcolumn chromatography (SiO₂-24 g, 30-100% EtOAc-hexanes) afforded(syn)-tert-butyl 1-oxohexahydrofuro[3,4-c]pyridine-5(3H)-carboxylate(3.1 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 4.27 (dd, J=9.4, 5.6 Hz, 1H),3.97 (dd, J=9.5, 2.0 Hz, 2H), 3.73 (s, 1H), 2.96-2.76 (m, 3H), 2.72-2.68(m, 1H), 2.01 (dq, J=13.9, 3.6 Hz, 1H), 1.90-1.82 (m, 1H), 1.44 (s, 9H).ESI-MS m/z calc. 241.1. found 242.5 (M+1)+; Retention time: 1.34 min. (3min run).

Step 2: tert-butyl1-oxo-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-3H-furo[3,4-c]pyridine-5-carboxylate

In an oven dried flask was added tert-butyl1-oxo-3,3a,4,6,7,7a-hexahydrofuro[3,4-c]pyridine-5-carboxylate (60 mg,0.25 mmol) which was put under an inert atmosphere (nitrogen) anddiluted with toluene (300 μL). The mixture was treated with Pd[P(tBu)₃]₂(6.3 mg, 0.012 mmol) and LiHMDS (300 μl of 1 M, 0.30 mmol), followed by2-bromopyridine (36 μl, 0.37 mmol). The reaction mixture was warmed to50° C. and stirred for 20 h. The reaction mixture was cooled to rt,diluted with saturated aqueous ammonium chloride and extracted withethyl acetate (3×). The combined organics were washed with saturatedaqueous NaCl, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification by reverse phase HPLC (1-100% ACN/H₂O) affordedtert-butyl1-oxo-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-3H-furo[3,4-c]pyridine-5-carboxylate(30 mg, 38%)¹H NMR (400 MHz, CDCl₃) δ 8.57 (ddd, J=4.8, 1.7, 0.8 Hz,1H), 7.73 (td, J=7.8, 1.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.25 (ddt,J=4.9, 2.9, 2.5 Hz, 1H), 4.33 (dd, J=9.2, 6.4 Hz, 1H), 4.03 (dd, J=9.2,4.2 Hz, 1H), 3.93 (dd, J=13.9, 5.4 Hz, 1H), 3.63-3.49 (m, 2H), 3.29-3.23(m, 2H), 2.26 (ddd, J=14.0, 5.2, 4.0 Hz, 1H), 2.20-2.06 (m, 1H), 1.47(s, 9H). ESI-MS m/z calc. 318.2. found 319.1 (M+1)+; Retention time:1.59 min (3 min run).

Step 3: tert-butyl3,4-bis(hydroxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate

A solution of tert-butyl1-oxo-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-3H-furo[3,4-c]pyridine-5-carboxylate(0.56 g, 1.76 mmol) in THF (6.5 mL) and toluene (2 mL) was treated withlithium borohydride (153 mg, 7.0 mmol). The reaction mixture was heatedto reflux for 2 h. The reaction mixture was cooled to 0° C. and dilutedwith DCM and ethyl acetate. The reaction mixture was quenched withsaturated aqueous ammonium chloride and 1 M HCl and the pH was adjustedto 8 with saturated aqueous sodium bicarbonate. The mixture wasextracted with DCM (3×) and the combined organics were dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Purification by flashcolumn chromatography (SiO₂-24 g, 40-100% ethyl acetate-DCM) affordedtert-butyl 3,4-bis(hydroxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate(400 mg, 70.5%). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (dd, J=4.9, 0.9 Hz, 1H),7.83-7.67 (m, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.22 (ddd, J=7.5, 4.9, 0.9Hz, 1H), 4.29-2.73 (m, 10H), 2.28 (s, 1H), 2.00-1.88 (m, 1H), 1.73 (ddd,J=14.0, 4.7, 3.5 Hz, 1H), 1.49 (s, 9H). ESI-MS m/z calc. 322.2. found323.5 (M+1)⁺; Retention time: 1.02 min (3 min run).

Step 4: tert-butyl7a-(2-pyridyl)-1,3,3a,4,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxylate

A solution of tert-butyl3,4-bis(hydroxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate (400 mg,1.24 mmol) and triphenylphosphine (391 mg, 1.49 mmol) in THF (12.4 mL)was cooled to 0° C. The reaction mixture was stirred for 1 h at 0° C.The reaction mixture was allowed to warm to rt and was concentratedunder reduced pressure. Purification by flash column chromatography(SiO₂-4 g, 30-100% EtOAc-hexanes) afforded tert-butyl7a-(2-pyridyl)-1,3,3a,4,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxylate(354 mg, 93.7%). ESI-MS m/z calc. 304.2. found 305.3 (M+1)⁺; Retentiontime: 1.2 min (3 min run).

Step 5:(3-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)(7a-(pyridin-2-yl)hexahydrofuro[3,4-c]pyridin-5(3H)-yl)methanone

A solution of tert-butyl7a-(2-pyridyl)-1,3,3a,4,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxylate(52 mg, 0.17 mmol) in DCM (0.5 mL) was treated with hydrogen chloride(500 μL of 4 M, 2.00 mmol) in dioxane. The reaction mixture was stirredfor 1 h and was concentrated under reduced pressure. The resulting crudeproduct was diluted with DMF (0.7 mL) and treated with HATU (78 mg, 0.21mmol) and 3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoic acid (48 mg,0.17 mmol). The mixture was treated with triethylamine (95 μL, 0.68mmol) and stirred for 1 h. The reaction mixture was filtered andpurified by reverse phase HPLC (Water, HCl-modifier, 1-100% ACN/H₂O, 30min) to afford(3-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)(7a-(pyridin-2-yl)hexahydrofuro[3,4-c]pyridin-5(3H)-yl)methanone(HCl salt) (25 mg, 29%)¹H NMR (400 MHz, C₆D₆) δ 8.53 (s, 1H), 7.21-7.04(m, 3H), 6.78-6.65 (m, J=7.7 Hz, 2H), 6.57 (d, J=8.1 Hz, 1H), 4.15-3.91(m, 4H), 3.86 (d, J=8.2 Hz, 1H), 3.81-3.70 (m, 4H), 3.68-3.58 (m, 2H),3.37 (s, 3H), 3.18-2.95 (m, 2H), 2.27-1.98 (m, 2H). ESI-MS m/z calc.466.17157. found 467.2 (M+1) MS m/z calc. 466.2. found 467.2 (M+1)⁺;Retention time: 0.964 min (3 min run).

tert-butyl(4aS,8aS)-8a-phenyl-2,3,4a,5,7,8-hexahydro-[1,4]dioxino[2,3-c]pyridine-6-carboxylate

A solution oftert-butyl(3R,4R)-3,4-dihydroxy-4-phenyl-piperidine-1-carboxylate (200mg, 0.68 mmol) and tetrabutylammonium hydrogensulfate (66 mg, 0.19 mmol)in dichloroethane (5 mL) was treated with NaOH (5 mL of 50% w/w inwater). The reaction mixture was stirred at 35° C. overnight and wascooled to rt and diluted with water and EtOAc. The organic layer wasseparated and the mixture was extracted with ethyl acetate (3×100 mL).The combined organics were washed with saturated aqueous NaCl, dried(Na₂SO₄), filtered, and concentrated under reduced pressure.Purification by flash column chromatography (SiO₂-12 g, 0-100% ethylacetate-hexanes) affordedtert-butyl(4aS,8aS)-8a-phenyl-2,3,4a,5,7,8-hexahydro-[1,4]dioxino[2,3-c]pyridine-6-carboxylate(86 mg, 40%)¹H NMR (400 MHz, CDCl₃) δ 7.55-7.27 (m, 5H), 4.34 (s, 1H),4.01 (ddd, J=11.9, 9.4, 4.2 Hz, 1H), 3.95-3.80 (m, 2H), 3.74-3.61 (m,2H), 3.46 (dt, J=11.8, 3.3 Hz, 1H), 3.37-3.23 (m, 2H), 2.12 (d, J=14.3Hz, 1H), 1.77-1.62 (m, 1H), 1.48 (s, 9H). ESI-MS m/z calc. 319.2. found320.3 (M+1); Retention time: 1.83 min (3 min run).

[(3aR,7aR)-2,2-dimethyl-7a-(2-pyridyl)-3a,4,6,7-tetrahydro[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanoneStep 1:[(3R,4R)-4-(6-bromo-2-pyridyl)-3,4-dihydroxy-1-piperidyl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone

Step 1: To a 100 mL round bottom flask was addedtert-butyl(3R,4R)-4-(6-bromo-2-pyridyl)-3,4-dihydroxy-piperidine-1-carboxylate(1.0 g, 2.7 mmol) and DCM (9 mL) followed by TFA (3 mL, 39 mmol). After1 h, the reaction mixture was concentrated under reduced pressure andused in the next step without purification.

Step 2: To a 100 mL round bottom flask was added3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoic acid (976 mg, 3.48mmol), HATU (1.0 g, 2.7 mmol), DMF (10 mL), and triethylamine (1.9 mL,13.4 mmol). The reaction mixture was allowed to stir at rt for 10 min.The amine from Step 1: was dissolved in DMF (3 mL) and added to thereaction mixture dropwise. The reaction mixture was allowed to stir atrt for 15 min. The reaction mixture was quenched with saturated aqueousNaCl, extracted with ethyl acetate (3×), and the combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The crude reaction mixture was purified via silica gel chromatography0%-75% ethyl acetate in DCM to provide[(3R,4R)-4-(6-bromo-2-pyridyl)-3,4-dihydroxy-1-piperidyl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone(1.4 g, 97%) as a thick yellow oil. ESI-MS m/z calc. 534.1. found 535.3(M+1)⁺; Retention time: 1.78 min (3 min run).

Step 2:[(3R,4R)-3,4-dihydroxy-4-(2-pyridyl)-1-piperidyl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone

To a 250 mL round bottom flask was added wet Pd/C (1.4 g, 1.3 mmol) andisopropanol (10 mL). The mixture was purged with nitrogen for 10 min andtreated with a solution of[(3R,4R)-4-(6-bromo-2-pyridyl)-3,4-dihydroxy-1-piperidyl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone(1.4 g, 2.6 mmol) in isopropanol (10 mL). The mixture was evacuated andput under hydrogen (1 atm, balloon). The reaction mixture was allowed tostir at 45° C. overnight. The reaction mixture was filtered and thefilter cake was washed with DCM and isopropanol. The solvent was removedand the product was isolated as a white foam. ¹H NMR (400 MHz, MeOD) δ8.53 (ddd, J=4.9, 1.7, 1.0 Hz, 1H), 7.86-7.80 (m, 1H), 7.78 (dt, J=8.0,1.2 Hz, 1H), 7.29 (ddd, J=7.3, 4.9, 1.4 Hz, 1H), 7.14 (s, 1H), 7.09-7.03(m, 2H), 4.55 (d, J=46.0 Hz, 1H), 4.40-4.33 (m, 2H), 4.29 (q, J=4.1 Hz,2H), 4.18 (s, 1H), 3.89 (s, 3H), 3.74 (d, J=25.1 Hz, 1H), 3.47 (dd,J=22.6, 21.0 Hz, 1H), 3.27-3.03 (m, 1H), 2.23 (s, 1H), 1.64 (t, J=50.8Hz, 1H). ESI-MS m/z calc. 456.4. found 457.5 (M+1)⁺; Retention time:1.32 min (3 min run).

Step 3:[(3aR,7aR)-2,2-dimethyl-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone

To a vial was added[(3R,4R)-3,4-dihydroxy-4-(2-pyridyl)-1-piperidyl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone(45 mg, 0.10 mmol) and dichloromethane (1 mL).[(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (2.3 mg,0.01 mmol) was added followed by 2,2-dimethoxypropane (36 μL, 0.30mmol). The reaction mixture was heated at 45° C. for 4 h. The reactionmixture was filtered and purified via HPLC (1%-99%) ACN:H2O with nomodifier to afford[(3aR,7aR)-2,2-dimethyl-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone(4.2 mg, 8.6%) as a white solid. ESI-MS m/z calc. 496.2. found 497.2(M+1)⁺; Retention time: 1.19 min (3 min run).

(1S,6R)-6-(2-pyridyl)-3-azabicyclo[4.1.0]heptane Step 1:(1R,2S)-2-(hydroxymethyl)-1-(2-pyridyl)cyclopropanecarbonitrile

To a suspension of sodium amide (8.6 g, 199.3 mmol) in anhydrous THF(225 mL) under nitrogen at −25° C. (external temp) was added dropwise asolution of 2-(2-pyridyl)acetonitrile (10.7 g, 90.6 mmol) in anhydrousTHF (50 mL) over 15 min. The cooling bath was removed and stirring wascontinued at rt for 2.5 h. A solution of (2S)-2-(chloromethyl)oxirane(21 mL, 272 mmol) in anhydrous THF (20 mL) was added at −25° C. in oneportion. The resulting reaction mixture was heated at 35° C. for 16 hand then at 50° C. for 20 h. After cooling to rt the reaction mixturewas poured into aqueous saturated aqueous ammonium chloride (100 mL),diluted with saturated aqueous NaCl (200 mL) and extracted with ethylacetate (4×250 mL). The combined organic phases were washed withsaturated aqueous NaCl (250 mL), dried over MgSO₄ and concentrated.Purification using silica gel chromatography (330 g silica, 10-30% ethylacetate in DCM, 60 min) afforded(1R,2S)-2-(hydroxymethyl)-1-(2-pyridyl)cyclopropanecarbonitrile (5.4 g,34%) as a yellow-orange solid. ¹H NMR (400 MHz, DMSO) δ 8.51 (ddd,J=4.8, 1.7, 0.9 Hz, 1H), 7.84 (td, J=7.8, 1.8 Hz, 1H), 7.57 (dt, J=7.9,0.9 Hz, 1H), 7.31 (ddd, J=7.5, 4.8, 1.0 Hz, 1H), 5.03 (t, J=5.2 Hz, 1H),3.84 (dt, J=11.9, 5.0 Hz, 1H), 3.49 (ddd, J=11.9, 8.4, 5.5 Hz, 1H), 2.13(dd, J=7.5, 5.1 Hz, 1H), 1.85 (dd, J=8.9, 4.6 Hz, 1H), 1.66 (dd, J=7.5,4.7 Hz, 1H). ESI-MS m/z calc. 174.1. found 175.1 (M+1)⁺; Retention time:0.39 min (3 min run).

Step 2:(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropanecarbonitrile

To a solution of (1R,2S)-2-(hydroxymethyl)-1-(2-pyridyl)cyclopropanecarbonitrile (5.4 g, 31.3 mmol) and imidazole (4.3 g, 62.5 mmol) inanhydrous DCM (65 mL) at 0° C. was addedtert-butyl-chloro-dimethyl-silane (4.9 g, 32 mmol) in portions over 5min. The cooling bath was removed and stirring was continued at rt for45 min. The reaction mixture was poured into saturated aqueous ammoniumchloride (100 mL), the phases were separated, and the aqueous phase wasextracted with DCM (3×100 mL). The combined organic extracts were driedover MgSO₄, filtered, and concentrated in vacuo. Purification usingsilica gel chromatography (330 g silica, 0-10% ethyl acetate in hexane,35 min) afforded(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropanecarbonitrile(8.2 g, 91%) as a colorless oil. ¹H NMR (400 MHz, DMSO) δ 8.45 (d, J=4.7Hz, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.26 (dd,J=6.8, 4.9 Hz, 1H), 4.03 (dd, J=11.6, 4.6 Hz, 1H), 3.62 (dd, J=11.6, 8.5Hz, 1H), 2.12 (qd, J=8.5, 4.6 Hz, 1H), 1.81 (dd, J=8.9, 4.7 Hz, 1H),1.68 (dd, J=7.4, 4.7 Hz, 1H), 0.80 (s, 9H), 0.00 (s, 3H), −0.02 (s, 3H).ESI-MS m/z calc. 288.2. found 289.5 (M+1)⁺; Retention time: 2.0 min (3min run).

Step 3:(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropanecarbaldehyde

A solution of(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropanecarbonitrile(6.2 g, 21 mmol) in anhydrous DCM (62 mL) at −78° C. under nitrogen wasadded dropwise to a solution of DIBAL-H (1M in toluene) (32 mL of 1 M,32 mmol) over 10 min. Stirring was continued at −78° C. for 1 h,followed by 1.5 h at rt. After cooling to −78° C. the reaction mixturewas quenched with isopropanol (62 mL) and allowed to warm up to rt.Dichloromethane (300 mL) and 50% aqueous saturated Rochelle's saltsolution (100 mL) was added, the phases were separated, and the organicphase was washed with 50% aqueous saturated Rochelles salt solution(2×100 mL). The combined aqueous phases were re-extracted with DCM (150mL). All combined organic phases were washed with water (100 mL) andsaturated aqueous NaCl (100 mL), dried over MgSO₄ and concentrated invacuo. Purification by silica gel chromatography (330 g silica, 0-20%MeOH in DCM, 40 min) afforded(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropanecarbaldehyde(2.7 g, 44%) as a yellow oil. ¹H NMR (400 MHz, DMSO) δ 9.75 (s, 1H),8.49 (dd, J=4.8, 0.8 Hz, 1H), 7.82-7.70 (m, 1H), 7.56 (d, J=8.0 Hz, 1H),7.26 (s, 1H), 4.04 (dd, J=11.5, 5.7 Hz, 1H), 3.62 (dd, J=11.5, 9.0 Hz,1H), 2.28 (qt, J=40.3, 20.1 Hz, 1H), 1.85 (dd, J=7.4, 4.4 Hz, 1H), 1.78(dd, J=8.6, 4.4 Hz, 1H), 0.87-0.71 (s, 9H), −0.00 (d, J=1.8 Hz, 6H).ESI-MS m/z calc. 291.2. found 292.3 (M+1)+; Retention time: 1.34 min (3min run).

Step 4:[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]methanol

To a solution of(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropanecarbaldehyde(3.6 g, 12.4 mmol) in anhydrous MeOH (100 mL) at −10° C. under nitrogenwas added NaBH₄ (470 mg, 12.4 mmol) in portions over 5 min. Stirring wascontinued at rt for 45 min, and the reaction mixture was cooled to 0° C.and quenched by addition of water (5 mL). Ethyl acetate (250 mL) andsaturated aqueous sodium bicarbonate (100 mL) were added, the phaseswere separated, and the aqueous phase was extracted with ethyl acetate(150 mL). The combined organic extracts were washed with saturatedaqueous NaCl (100 mL), dried over MgSO₄ and concentrated to afford[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]methanol(3.6 g, 99%) as a yellow oil. ¹H NMR (400 MHz, DMSO) δ 8.42-8.32 (m,1H), 7.68-7.58 (m, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.14-7.03 (m, 1H),4.42-4.37 (m, 1H), 3.97-3.92 (m, 1H), 3.88-3.68 (m, 3H), 1.75-1.56 (m,1H), 1.30 (dd, J=8.7, 3.8 Hz, 1H), 0.85 (dd, J=6.2, 3.9 Hz, 1H), 0.80(s, 9H), 0.00 (s, 3H), −0.02 (s, 3H). ESI-MS m/z calc. 293.2. found294.5 (M+1)⁺; Retention time: 1.16 min (3 min run).

Step 5:[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]methylmethanesulfonate

[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]methanol(1.5 g, 5.2 mmol) was dissolved in DCM (24 mL), cooled to −10° C., thentreated with DIEA (1.1 mL, 6.3 mmol) and dropwise with MsCl (450 μL, 5.7mmol). The reaction mixture was stirred at 0° C. for 1.5 h then allowedto warm to rt. The reaction mixture was concentrated and purified bysilica gel chromatography (80 g silica, 0-50% ethyl acetate/hexane) toprovide[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]methylmethanesulfonate (1.6 g, 84%) as a colorless oil. ¹H NMR (400 MHz, DMSO)δ 8.48 (ddd, J=4.8, 1.7, 0.8 Hz, 1H), 7.74 (td, J=7.8, 1.8 Hz, 1H), 7.40(d, J=8.1 Hz, 1H), 7.20 (ddd, J=7.5, 4.8, 0.8 Hz, 1H), 4.86 (d, J=10.8Hz, 1H), 4.71 (d, J=10.8 Hz, 1H), 3.92 (dd, J=11.6, 6.1 Hz, 1H), 3.83(dd, J=11.5, 7.3 Hz, 1H), 3.19 (s, 3H), 1.84 (dt, J=13.7, 6.7 Hz, 1H),1.52 (dd, J=8.8, 4.3 Hz, 1H), 1.18 (dd, J=6.6, 4.4 Hz, 1H), 0.86 (s,9H), 0.06 (s, 3H), 0.03 (s, 3H).

Step 6:2-[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]acetonitrile

A mixture of[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]methylmethanesulfonate (870 mg, 2.34 mmol) and NaCN (126 mg, 2.58 mmol) inanhydrous DMSO (8.7 mL) under a nitrogen atmosphere was stirred at rtovernight for 16 h. The reaction mixture was diluted with ethyl acetate(200 mL) and washed with 50% saturated sodium bicarbonate solution (100mL), water (100 mL), and saturated aqueous NaCl (100 mL). The organiclayer was dried over MgSO₄ and concentrated. Purification by silica gelchromatography (120 g silica, 10-50% ethyl acetate/hexane) afforded2-[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]acetonitrile(518 mg, 73.1%) as a colorless oil. ¹H NMR (400 MHz, DMSO) δ 8.44 (dd,J=4.8, 0.9 Hz, 1H), 7.73-7.67 (m, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.18-7.13(m, 1H), 3.99-3.86 (m, 1H), 3.72 (dd, J=11.6, 7.8 Hz, 1H), 3.14 (d,J=17.3 Hz, 1H), 3.05 (d, J=17.3 Hz, 1H), 1.66 (dt, J=14.4, 7.2 Hz, 1H),1.36 (dd, J=9.2, 4.6 Hz, 1H), 0.99 (dd, J=6.6, 4.6 Hz, 1H), 0.55 (s,9H), −0.00 (s, 3H), −0.02 (s, 3H). ESI-MS m/z calc. 302.2. found 303.3(M+1)⁺; Retention time: 1.52 min (3 min run).

Step 7:2-[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]ethanamine

To a solution of2-[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]acetonitrile(250 mg, 0.83 mmol) in anhydrous THF (7.5 mL) at 0° C. under nitrogenwas added a solution of borane-tetrahydrofuran complex (2.5 mL of 1 M,2.5 mmol) in THF dropwise over 5 min. The resulting mixture was heatedat reflux for 2 h. After cooling to 0° C., MeOH (0.75 mL) was addedcarefully, and the mixture was heated again at reflux for 1 h. Aftercooling to rt the reaction mixture was concentrated, the residueredissolved in DCM (50 mL), washed with water (30 mL), saturated aqueousNaCl (30 mL), dried over MgSO₄ and concentrated. Purification usingsilica gel chromatography (40 g silica, 0-20% MeOH in DCM with 2%triethylamine, 30 min) afforded2-[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]ethanamine(124 mg, 49%) as a colorless oil. ¹H NMR (400 MHz, DMSO) δ 8.47 (d,J=4.5 Hz, 1H), 7.75-7.68 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.24-7.12 (m,1H), 4.07-3.85 (m, 1H), 3.63-3.55 (m, 1H), 3.00-2.90 (m, 1H), 2.87-2.75(m, 3H), 2.40-2.16 (m, 1H), 2.16-1.95 (m, 1H), 1.64-1.55 (m, 1H),1.32-1.26 (m, 1H), 0.85 (s, 9H), 0.81-0.73 (m, 1H), 0.06 (s, 3H), 0.03(s, 3H). ESI-MS m/z calc. 306.2. found 307.3 (M+1)⁺; Retention time:1.04 min (3 min run).

Step 8: [(1S,2R)-2-(2-aminoethyl)-2-(2-pyridyl)cyclopropyl]methanol

To a solution of2-[(1R,2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-pyridyl)cyclopropyl]ethanamine(124 mg, 0.40 mmol) in anhydrous THF (2.5 mL) under nitrogen at rt wasadded a solution of tetra-n-butylammonium fluoride (0.4 mL of 1 M, 0.40mmol) in THF dropwise over 5 min. The reaction mixture was continued tostir at rt for 2.5 h. Additional tetra-n-butylammonium fluoride (50 μLof 1 M, 0.05 mmol) in THF was added, and the reaction mixture wascontinued to stir at rt for 30 min. The reaction mixture wasconcentrated and purified using silica gel chromatography (24 g silica,0-20% MeOH in DCM w/2.5% triethylamine, 20 min). After concentration ofproduct fractions the residue was coconcentrated under reduced pressurewith acetonitrile (3×10 mL) to remove traces of triethylamine to afford[(1S,2R)-2-(2-aminoethyl)-2-(2-pyridyl)cyclopropyl]methanol (54 mg, 69%)ESI-MS m/z calc. 192.1. found 193.5 (M+1)⁺; Retention time: 0.26 min (3min run).

Step 9: (1S,6R)-6-(2-pyridyl)-3-azabicyclo[4.1.0]heptane

To a suspension of[(1S,2R)-2-(2-aminoethyl)-2-(2-pyridyl)cyclopropyl]methanol (54 mg, 0.28mmol) in anhydrous DCE (2.5 mL) under nitrogen at 0° C. was added SOCl₂(25 μL, 0.34 mmol) dropwise. The resulting reaction mixture was stirredat rt for 4 h. After cooling to 0° C. additional SOCl₂ (102 μL, 1.40mmol). The reaction mixture was concentrated, dissolved in water (20mL), and adjusted to basic pH with 3.75 M aqueous NaOH The aqueous phasewas extracted with DCM (5×40 mL) and the combined organic extracts weredried over MgSO₄, filtered, and concentrated to afford crude(1S,6R)-6-(2-pyridyl)-3-azabicyclo[4.1.0]heptane (42 mg, 86%). ESI-MSm/z calc. 174.2. found 175.1 (M+1)⁺; Retention time: 0.368 min (3 minrun).

tert-butyl7,7-difluoro-6-(2-pyridyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

To a 4 ml vial charged with a magnetic stirbar was added tert-butyl4-(2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (235 mg, 0.90 mmol),sodium iodide (45 mg, 0.30 mmol) and anhydrous THF (1.5 mL) in undernitrogen atmosphere. To this was added trimethyl-(trifluoromethyl)silane(470 μL, 3.2 mmol). The reaction vessel was sealed and heated to 65° C.for 17 h. The volatiles were removed under reduced pressure and theresulting. residue was purified by flash chromatography on silica gel(24 g column) using a gradient of AcOEt (0 to 60% over 25 min) inhexanes to provide tert-butyl7,7-difluoro-6-(2-pyridyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (64mg, 22.4%) as a brown viscous oil. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d,J=4.3 Hz, 1H), 7.68 (td, J=7.7, 1.8 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H),7.20 (ddd, J=7.5, 4.9, 1.0 Hz, 1H), 3.91 (br s, 1H), 3.80 (br s, 1H),3.70-3.40 (br m, 1H), 3.25-3.00 (br m, 1H), 2.60-2.50 (m, 1H), 2.34 (brs, 1H), 2.21-2.05 (m, 1H), 1.47 (s, 9H). ESI-MS m/z calc. 310.1. found311.0 (M+1)⁺; Retention time: 1.02 min (3 min run).

tert-butyl(1R,6R)-6-(2-pyridyl)-8-oxa-3-azabicyclo[4.2.0]octane-3-carboxylate(racemic) Step 1: tert-butyl6-(2-pyridyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

A solution of tert-butyl4-(2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (15.1 g, 58.1 mmol)in 1,4-dioxane (100 mL), and water (150 mL) was treated withN-bromosuccinimide (15.5 g, 87.1 mmol). The reaction mixture was allowedto stir at rt for 1 h. An aqueous solution of sodium hydroxide (116 mLof 1 M, 116 mmol) was added, and the reaction mixture was stirred for anadditional 15 min. The mixture was extracted with ethyl acetate (3×75mL). The organic layers were combined, dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting orangeoil was purified by silica gel column chromatography: 220 gram silicagel column, 0-40% ethyl acetate/hexane gradient; product eluted at 20%to provide tert-butyl6-(2-pyridyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (11.5 g,72%) as a clear yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=4.1 Hz,1H), 7.70 (td, J=7.8, 1.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.22 (ddd,J=7.5, 4.8, 1.1 Hz, 1H), 3.90 (dt, J=24.8, 14.3 Hz, 2H), 3.66 (s, 1H),3.30 (d, J=2.4 Hz, 2H), 2.83 (s, 1H), 2.16 (s, 1H), 1.47 (s, 9H). ESI-MSm/z calc. 276.1. found 277.3 (M+1)⁺; Retention time: 0.96 min (3 minrun).

Step 2: provide tert-butyl4-cyano-3-hydroxy-4-(2-pyridyl)piperidine-1-carboxylate

To a solution of tert-butyl6-(2-pyridyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (14.4 g,52.2 mmol) in DMSO (216 mL) was added potassium cyanide (10.2 g, 157mmol). The reaction mixture was heated at 90° C. for 24 h, cooled to rt,and partitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate (3×). The combined organic layers werewashed with water (3×), saturated aqueous NaCl, dried over MgSO₄,filtered and concentrated to dryness. Purification by flash columnchromatography (SiO₂-80 g, 0-100% ethyl acetate-hexanes) affordedtert-butyl 4-cyano-3-hydroxy-4-(2-pyridyl)piperidine-1-carboxylate (3.5g, 22%). ESI-MS m/z calc. 303.2. found 304.1 (M+1)⁺; Retention time:1.48 min (3 min run).

Step 3:tert-butyl(3R,4R)-3-benzyloxy-4-cyano-4-(2-pyridyl)piperidine-1-carboxylate

To a solution of tert-butyl4-cyano-3-hydroxy-4-(2-pyridyl)piperidine-1-carboxylate (2.2 g, 7.1mmol) in DMF (20 mL) was added sodium hydride (340 mg, 8.5 mmol). Thereaction mixture was stirred at rt for 15 min and was treated withbenzylbromide (1.0 mL, 8.5 mmol). The reaction mixture was stirred at rtovernight and then partitioned between ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate (3×), and the combinedorganic layers were washed with water (3×), saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated to dryness. The crudematerial was purified by column chromatography (0-20% ethylacetate-hexanes) to providetert-butyl(3R,4R)-3-benzyloxy-4-cyano-4-(2-pyridyl)piperidine-1-carboxylate(2.6 g, 93%). ESI-MS m/z calc. 393.5. found 394.5 (M+1)⁺; Retentiontime: 2.14 min (3 min run).

Step 4: O1-tert-butylO4-methyl(3R,4S)-3-benzyloxy-4-(2-pyridyl)piperidine-1,4-dicarboxylate

To a solution of tert-butyl3-benzyloxy-4-cyano-4-(2-pyridyl)piperidine-1-carboxylate (2.4 g, 6.1mmol) in EtOH (20 mL) was added KOH (20 mL of 50% w/w in water). Thereaction mixture was heated at 120° C. for 25 h and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×) andthe combined organic layers were washed with saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated to dryness. The crudeproduct3-benzyloxy-1-tert-butoxycarbonyl-4-(2-pyridyl)piperidine-4-carboxylicacid (2.4 g, 5.8 mmol) was dissolved in DMF (30 mL) and was treated withsodium hydride (349 mg, 8.7 mmol)(60% dispersion in mineral oil). Thereaction mixture was stirred at rt for 15 min and was treated withiodomethane (543 μL, 8.73 mmol). The reaction mixture was stirred at rtfor 2 h and was partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc (3×), the combined organic layers were washedwith water (3×), saturated aqueous NaCl, dried (MgSO₄), filtered andconcentrated to dryness. The crude material was purified by columnchromatography (0-20% EtOAc-Hex) to provide O-1-tert-butylO4-methyl(3R,4S)-3-benzyloxy-4-(2-pyridyl)piperidine-1,4-dicarboxylate(1.1 g, 44%). ESI-MS m/z calc. 426.5. found 427.5 (M+1)⁺; Retentiontime: 2.13 min (3 min run).

Step 5:tert-butyl(3R,4R)-3-benzyloxy-4-(methylsulfonyloxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate

Step 1: To a refluxing solution of O1-tert-butylO4-methyl(3R,4S)-3-benzyloxy-4-(2-pyridyl)piperidine-1,4-dicarboxylate(1.1 g, 2.6 mmol) in THF (30 mL) was added lithium aluminum hydride (1.5mL of 2 M in THF, 3.1 mmol). The mixture was heated at reflux for 1 minand was cooled to 0° C. The reaction mixture was quenched sequentiallywith water (5 drops), 15% aqueous NaOH (5 drops) and water (15 drops).The resulting white precipitate was removed via filtration and washedwith EtOAc. The filtrate was dried over MgSO₄, filtered and concentratedto dryness. The crude material was used directly in next step withoutfurther purification. To a solution of tert-butyl3-benzyloxy-4-(hydroxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate (200mg, 0.50 mmol) in DCM (10 mL) was added triethylamine (210 μL, 1.51mmol) followed by the addition of methanesulfonyl chloride (58 μl, 0.75mmol). The reaction mixture was stirred at rt for 5 min, diluted withDCM, washed with water (3×), dried over MgSO₄, filtered and concentratedto dryness. The crude material was purified by column chromatography toprovidetert-butyl(3R,4R)-3-benzyloxy-4-(methylsulfonyloxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate(210 mg, 88%). ESI-MS m/z calc. 386.5. found 387.5 (M+1)⁺; Retentiontime: 1.34 min (3 min run).

Step 6:tert-butyl(3R,4R)-3-hydroxy-4-(methylsulfonyloxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate

To a solution of tert-butyl3-benzyloxy-4-(methylsulfonyloxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate(200 mg, 0.42 mmol) in MeOH (20 mL) was added ammonium formate (530 mg,8.4 mmol) and 10% Pd/C (92 mg, 0.09 mmol). The reaction mixture washeated at reflux for 10 min. The catalyst was removed via filtrationthrough celite and washed with MeOH. The filtrate was concentrated todryness. The residue was purified by column chromatography to providetert-butyl(3R,4R)-3-hydroxy-4-(methylsulfonyloxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate(105 mg, 65%) ESI-MS m/z calc. 386.5. found 387.5 (M+1)⁺; Retentiontime: 1.34 min (3 min run).

Step 7:tert-butyl(1R,6R)-6-(2-pyridyl)-8-oxa-3-azabicyclo[4.2.0]octane-3-carboxylate

To a solution oftert-butyl(3R,4R)-3-hydroxy-4-(methylsulfonyloxymethyl)-4-(2-pyridyl)piperidine-1-carboxylate(100 mg, 0.26 mmol) in toluene (6 mL) was added DBU (46 μL, 0.31 mmol)The reaction mixture was heated at 120° C. for 16 h, diluted with ethylacetate, washed with water (3×), dried over MgSO₄, filtered, andconcentrated to dryness. The crude material was purified by columnchromatography to providetert-butyl(1R,6R)-6-(2-pyridyl)-8-oxa-3-azabicyclo[4.2.0]octane-3-carboxylate(42 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (ddd, J=4.9, 1.7, 0.9 Hz,1H), 7.70 (t, J=7.7 Hz, 1H), 7.19 (ddd, J=7.5, 4.9, 0.8 Hz, 1H), 7.09(t, J=8.7 Hz, 1H), 5.39-5.23 (m, 1H), 4.99 (t, J=6.1 Hz, 1H), 4.72 (d,J=6.0 Hz, 1H), 4.18-3.78 (m, 3H), 3.47 (ddd, J=22.2, 15.4, 1.9 Hz, 1H),2.20-2.07 (m, 2H), 1.48 (t, J=10.4 Hz, 10H). ESI-MS m/z calc. 290.2.found 291.5 (M+1)⁺; Retention time: 1.17 min. (3 min run).

tert-butyl(3aR,7aR)-7a-(4-methoxy-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate

In a 100 mL round bottom flask equipped with a septa,tert-butyl(3aR,7aR)-7a-(6-chloro-4-methoxy-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(1.09 g, 2.94 mmol) and triethylamine (410 μL, 2.94 mmol) were dissolvedin ethanol (20 mL). Palladium (156 mg, 0.15 mmol) (10% on carbon) wasadded, and the mixture was degassed by bubbling nitrogen gas. Thereaction mixture was vigorously stirred under hydrogen atmosphere(balloon) for 5 h. The suspension was degassed by bubbling nitrogen. Thecatalyst was removed by filtration through a pad of celite. The solidwas thoroughly washed with ethanol. The filtrate was concentrated underreduce pressure to provide a the crude product. Purification by flashchromatography on silica gel (40 g column) using a gradient of AcOEt(0-100% over 20 min). providedtert-butyl(3aR,7aR)-7a-(4-methoxy-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylate(907 mg, 91.7%) as a colorless oil that started to crystallize uponstanding. ESI-MS m/z calc. 336.2. found 337.0 (M+1)⁺; Retention time:1.64 min (3 min run).

6-ethoxy-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylic acid Step1: 6-chloro-5-hydroxy-pyridine-2-carbonitrile

2-chloro-6-iodo-pyridin-3-ol (2.0 g, 7.8 mmol) was dissolved in DMF (15mL), and dicyanozine (0.7 g, 5.9 mmol) was added. Nitrogen gas wasbubbled through the reaction mixture before and after the addition oftriphenylphosphine palladium (0) (0.6 g, 0.55 mmol). The reaction vesselwas sealed under nitrogen and heated under microwave irradiation at 100°C. for 30 min. Volatiles were removed under reduced pressure. Theremaining oil was dissolved in ethyl acetate (100 mL) and washed withwater (100 mL) followed by saturated aqueous NaCl (2×100 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure to provide a crystalline solid. Purification bysilica gel column chromatography: 40 gram silica gel column, 0-50% ethylacetate/hexane gradient over 20 min; provided6-chloro-5-hydroxy-pyridine-2-carbonitrile (0.8 g, 63%) as a crystallineyellow-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.59 (m, 1H), 7.42(d, J=8.2 Hz, 1H). ESI-MS m/z calc. 154.0. found 155.0 (M+1)⁺; Retentiontime: 0.72 min (3 min run).

Step 2: methyl 6-chloro-5-hydroxy-pyridine-2-carboxylate

6-chloro-5-hydroxy-pyridine-2-carbonitrile (7.1 g, 45.8 mmol) wasdissolved in methanol (25 mL), and a solution of HCl (100 mL of 4 M,400.0 mmol) in dioxane was added. The reaction mixture was stirred in apre-heated 80° C. oil bath for 36 h. Additional methanol and HCl/dioxanewas sequentially added to help progress the reaction. Volatiles wereremoved under reduced pressure to obtain a yellow solid which wasfiltered through a plug of silica gel. The filtrate was concentrated anddissolved in 1,4-dioxane (50 mL) at 65° C. Hot hexane (75 mL) was addedto the solution, and the resulting slurry was allowed to slowly cool tort. The crystalline solids were collected by vacuum filtration, rinsingwith hexane. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.3 Hz, 1H), 7.47-7.40(m, 1H), 6.13 (s, 1H), 3.98 (s, 3H). ESI-MS m/z calc. 187.0. found 188.3(M+1)⁺; Retention time: 0.36 min (3 min run).

Step 3: methyl6-chloro-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylate

A solution of methyl 6-chloro-5-hydroxy-pyridine-2-carboxylate (2.5 g,13.3 mmol) in DMF (15 mL) was treated slowly with sodium hydride (0.5 g,12.6 mmol) (60 wt % dispersion in mineral oil) portionwise. The reactionmixture was allowed to stir at rt for 15 min and cooled to −10° C. priorto the slow dropwise addition of neat 2-(trifluoromethoxy)ethyltrifluoromethanesulfonate (4.5 g, 17.3 mmol) over 5 min. An exotherm wasobserved during addition. The reaction mixture was then allowed toslowly warm to rt and stirred for 1 h. Water (10 mL) was added, and themixture was concentrated under reduced pressure. The remaining residuewas resuspended in water (75 mL) and extracted with ethyl acetate (3×75mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure. The remaining solidwas briefly stirred in DCM (50 mL), and the remaining white solids wereremoved by vacuum filtration. The filtrate was again concentrated underreduced pressure and purified by silica gel column chromatography: 80gram silica gel column, 0-40% ethyl acetate/hexane gradient over 30 min;product eluted at 30%. Pure fractions were combined and concentrated toafford methyl6-chloro-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylate (2.9 g,74%) as a light brown crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 8.10(d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.45-4.38 (m, 2H), 4.36 (dd,J=5.8, 3.4 Hz, 2H), 3.98 (s, 3H). ESI-MS m/z calc. 299.0. found 300.4(M+1)⁺; Retention time: 1.47 min (3 min run).

Step 4: 6-ethoxy-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylicacid

A solution of methyl6-chloro-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylate (250 mg,0.83 mmol) in 1,4-dioxane was treated with sodium ethanolate (2.0 mL of21% w/v, 6.2 mmol) and water (50 μL, 2.78 mmol). The reaction mixturewas heated under microwave irradiation at 100° C. for 1 h. The reactionmixture was partioned between ethyl acetate (75 mL) and water (50 mL).The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified byUV-triggered reverse-phase HPLC: 10-99% acetonitrile/water gradient over15 min to provide6-ethoxy-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylic acid (18mg, 7.3%) as a light brown foaming solid. ¹H NMR (400 MHz, CDCl₃) δ 7.82(d, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 4.36(dt, J=15.8, 4.1 Hz, 4H), 1.49 (t, J=7.1 Hz, 3H). ESI-MS m/z calc.295.1. found 296.4 (M+1)⁺; Retention time: 1.38 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor 6-ethoxy-5-[2- methyl 6-chloro-5-hydroxy-(trifluoromethoxy)ethoxy]pyridine-2- pyridine-2-carboxylate carboxylicacid 6-methoxy-5-[2- methyl 6-chloro-5-hydroxy-(trifluoromethoxy)ethoxy]pyridine-2- pyridine-2-carboxylate carboxylicacid

5-(2-fluoro-2-methyl-propoxy)-6-methoxy-pyridine-2-carboxylic acid Step1: methyl 6-chloro-5-(2-hydroxy-2-methyl-propoxy)pyridine-2-carboxylate

A solution of methyl 6-chloro-5-hydroxy-pyridine-2-carboxylate (1.6 g,8.3 mmol) in methanol (1.5 mL) was treated with finely ground potassiumcarbonate (4.6 g, 33.0 mmol). The reaction mixture was heated to 80° C.and 1-chloro-2-methyl-propan-2-ol (1.7 mL, 16.5 mmol) was added. Thereaction mixture was heated at 80° C. overnight. The reaction mixturewas concentrated under reduced pressure. The remaining residue wassuspended in water (75 mL) and extracted with ethyl acetate (2×75 mL).Organic layers were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting oil was purified bysilica gel column chromatography: 40 gram silica gel column, 0-30% ethylacetate/hexane gradient over 25 min to afford methyl6-chloro-5-(2-hydroxy-2-methyl-propoxy)pyridine-2-carboxylate (1.2 g,54%) was obtained as a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ 8.09(d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 2H),1.41 (s, 6H). ESI-MS m/z calc. 259.1. found 260.2 (M+1)+; Retentiontime: 0.99 min (3 min run).

Step 2: methyl6-chloro-5-(2-fluoro-2-methyl-propoxy)pyridine-2-carboxylate

A solution of methyl6-chloro-5-(2-hydroxy-2-methyl-propoxy)pyridine-2-carboxylate (500 mg,1.93 mmol) in DCM, and2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-4-sulfanyl)ethanamine (391 μL,2.12 mmol) was slowly added at rt. A water bath was used to maintain thereaction mixture near rt. After 2 h, the reaction mixture was dilutedwith DCM (75 mL) and washed with water (1×75 mL). The aqueous layer wasfurther extracted with DCM (2×75 mL). All organic layers were combined,dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography: 12 gram silica gel column, 0-40% ethyl acetate/hexanegradient over 20 min to provide methyl6-chloro-5-(2-fluoro-2-methyl-propoxy)pyridine-2-carboxylate (170 mg,34%) was obtained as a clear colorless oil that crystallized uponstanding. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=8.4 Hz, 1H), 7.28 (d,J=8.4 Hz, 1H), 4.09 (d, J=16.5 Hz, 2H), 3.98 (s, 3H), 1.60-1.52 (m, 6H).ESI-MS m/z calc. 261.1. found 262.2 (M+1)⁺; Retention time: 1.41 min (3min run).

Step 3: 5-(2-fluoro-2-methyl-propoxy)-6-methoxy-pyridine-2-carboxylicacid

A solution of methyl6-chloro-5-(2-fluoro-2-methyl-propoxy)pyridine-2-carboxylate (170 mg,0.65 mmol) in 1,4-dioxane (2 mL) was treated with sodium methoxide (3.00mL of 0.5 M, 1.500 mmol) in methanol followed by water (50 μL, 2.78mmol). The reaction mixture was heated by microwave irradiation at 100°C. for 1 h, then at 120° C. for 30 min. Volatiles were removed underreduced pressure, and the remaining solid was dissolved in water (20 mL)and adjusted to pH 2 with the addition of aqueous 1 N HCl solution. Theresulting solution was extracted with DCM (3×50 mL). Organic layers werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure to a clear colorless oil. Purification by reverse-phaseHPLC (1-99% acetonitrile water gradient over 15 min) provided5-(2-fluoro-2-methyl-propoxy)-6-methoxy-pyridine-2-carboxylic acid.ESI-MS m/z calc. 243.1. found 244.3 (M+1)⁺; Retention time: 1.14 min (3min run).

5-(2-fluoro-2-methyl-propoxy)-6-methoxy-pyridine-2-carboxylic acid

A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL),4-hydroxy-3-methyl-benzoic acid (2.0 g, 13.2 mmol), K₂CO₃ (7.3 g, 52.7mmol), H₂O (6.0 mL) and ethanol (60 mL) was heated at 80° C. overnight.The reaction mixture was cooled to rt, partitioned between 1N NaOH andEtOAc and the layers separated. The organic layer was washed with 1NNaOH (2×) and the combined aqueous layers were washed with EtOAc. Thecombined organics were concentrated under reduced pressure and dilutedwith EtOH (15 mL). The mixture was treated with H₂O (2 mL) and NaOH (1.0g, 26.3 mmol). The reaction mixture was stirred at 40° C. for 4 h. Thereaction mixture was poured into 1N NaOH and extracted with ether (2×).The pH was brought to 2-3 with 6N HCl and the aqueous material wasextracted with EtOAc (3×). The organics were combined, washed withsaturated aqueous NaCl, dried (Na₂SO₄), filtered, and evaporated todryness. The material was triturated with ether to provide4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid (2.2 g, 75%) as awhite solid. ¹H NMR (400 MHz, DMSO) δ 7.75 (dd, J=8.5, 2.0 Hz, 1H),7.73-7.70 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.67 (s, 1H, OH), 3.76 (s,2H), 2.20 (s, 3H), 1.22 (s, 6H). ESI-MS m/z calc. 224.1. found 225.5(M+1)⁺; Retention time: 1.06 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor 4-(2-hydroxy-2-methylpropoxy)- methyl4-(2-hydroxy-2-methylpropoxy)- 3-methylbenzoic acid 3-methylbenzoate4-(2-hydroxy-2-methylpropoxy)- methyl 4-(2-hydroxy-2-methylpropoxy)-3-methoxybenzoic acid 3-methoxybenzoate 4-(2-hydroxy-2-methylpropoxy)-methyl 4-(2-hydroxy-2-methylpropoxy)- 3-chlorobenzoic acid3-chlorobenzoate

6-methyl-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylic acid Step1: methyl 6-methyl-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylate

A solution of methyl 5-hydroxy-6-methyl-pyridine-2-carboxylate (2.0 g,12.1 mmol) in DMF (12 mL) was cooled to 0° C. before the slow additionof sodium hydride (0.5 g, 11.5 mmol) (60 wt % dispersion in mineraloil). The reaction mixture was allowed to stir at rt for 10 min beforeit was cooled to −10° C. 2-(trifluoromethoxy)ethyltrifluoromethanesulfonate (4.1 g, 15.8 mmol) was slowly added neat tothe reaction mixture over 5 min. An exotherm was observed during theaddition. The reaction mixture was allowed to stir at rt for 1 h. Water(50 mL) was added to the reaction mixture, and it was concentrated underreduced pressure. The remaining solid was partitioned between ethylacetate (75 mL) and water (75 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography: 5-20%ethyl acetate/hexane gradient providing methyl6-methyl-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylate (1.6 g,48%) as a light brown crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 8.02(d, J=8.4 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 4.38 (dd, J=5.6, 3.5 Hz, 2H),4.30-4.26 (m, 2H), 3.98 (s, 3H), 2.57 (s, 3H). ESI-MS m/z calc. 279.1.found 280.3 (M+1)⁺; Retention time: 1.29 min (3 min run).

Step 2: 6-methyl-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylicacid

To a solution of methyl6-methyl-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylate (1.6 g,5.9 mmol) in methanol (10 mL) was added a solution of sodium hydroxide(2.3 g, 58.7 mmol) in water (5 mL). The reaction mixture was stirred at45° C. for 30 min. After cooling to rt, it was acidified to pH 5 withthe addition of an aqueous 1 N HCl solution. The mixture was extractedwith DCM (3×50 mL). The organic layers were combined, dried over sodiumsulfate, filtered and concentrated under reduced pressure to provide6-methyl-5-[2-(trifluoromethoxy)ethoxy]pyridine-2-carboxylic acid (1.5g, 94%) as a white powder. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.4 Hz,1H), 7.24 (t, J=10.5 Hz, 1H), 4.39 (d, J=3.9 Hz, 2H), 4.29 (t, J=13.6Hz, 2H), 2.53 (s, 3H). ESI-MS m/z calc. 265.1. found 266.3 (M+1)⁺;Retention time: 0.78 min (3 min run).

5-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyridine-2-carboxylic acid

To a solution of methyl6-chloro-5-(2-hydroxy-2-methyl-propoxy)pyridine-2-carboxylate (200 mg,0.77 mmol) in 1,4-dioxane (1 mL) was added a solution of sodiummethoxide (3 mL of 0.5 M, 1.5 mmol) in methanol, followed by water (50μL, 2.8 mmol). The reaction mixture was heated under microwaveirradiation at 100° C. for 1 h. Volatiles were removed under reducedpressure, and the remaining solid was dissolved in water (20 mL) andadjusted to pH 2 with the addition of aqueous 1 N HCl solution. Theresulting solution was extracted with DCM (3×50 mL) and the organiclayers were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to provide a colorless oil.Purification by reverse-phase HPLC (1-99% acetonitrile water gradientover 15 min) provided5-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyridine-2-carboxylic acid (49mg, 24%). ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J=8.0 Hz, 1H), 7.20 (d,J=8.0 Hz, 1H), 4.06 (s, 3H), 3.89 (s, 2H), 1.39 (s, 6H). ESI-MS m/zcalc. 241.1. found 242.3 (M+1)⁺; Retention time: 0.77 min (3 min run).

2-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid Step 1: methyl2-(methylsulfanylcarbothioyloxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylate

To methyl 2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylate(0.9 g, 4.0 mmol) and tetrabutylammonium sulfate (186 μL, of 50% w/v,0.16 mmol) under N₂ was added NaOH (8 mL of 50% w/v in H₂O, 100.0 mmol)portionwise. The viscous mixture was stirred for 10 min and CS₂ (7.2 mL,120.0 mmol) was added dropwise followed by iodomethane (18.8 g, 132.5mmol). The viscous biphasic mixture was stirred overnight, diluted withwater (20 mL), and the organic layer was separated. The aqueous mixturewas extracted with dichloromethane (3×20 mL). The combined organics werewashed with saturated aqueous NaCl (2×10 mL), dried over MgSO₄,evaporated and purified by column chromatography to provide methyl2-(methylsulfanylcarbothioyloxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 7.64-7.54 (m, 2H), 6.99-6.89 (m, 1H), 4.83(qd, J=11.8, 5.2 Hz, 2H), 4.69-4.60 (m, 1H), 4.37 (dd, J=11.6, 2.4 Hz,1H), 4.14 (dd, J=11.6, 6.8 Hz, 1H), 3.88 (s, 3H), 2.59 (s, 3H).

Step 2: methyl2-((trifluoromethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate

To a suspension of 5,5-dimethyl-1,3-dibromohydantoin (860 mg, 3.0 mmol)in DCM (5 mL) was added pyridine (hydrofluoric acid) (870 μL of 70% w/w,6.0 mmol) at −78° C. dropwise under Ar. The reaction mixture was stirredat −78° C. for 5 min and treated with methyl2-(methylsulfanylcarbothioyloxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylate(157 mg, 0.50 mmol) in DCM (2 mL) dropwise. The reaction mixture wasstirred at −78° C. for 15 min. The cooling bath was removed and thereaction mixture was allowed to warm to rt and the mixture was stirredat rt overnight. Water was added and the mixture was extracted with DCM(2×). The combined organic layers were dried over MgSO₄, filtered andconcentrated to dryness. The crude material was purified by columnchromatography (0-10%) to provide methyl5,6,8-tribromo-3-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-7-carboxylate(180 mg, 68%). ¹H NMR (400 MHz, CDCl₃) δ 4.58 (d, J=6.5 Hz, 1H), 4.47(dd, J=11.8, 2.5 Hz, 1H), 4.24 (tdd, J=10.1, 8.4, 4.1 Hz, 3H), 3.97 (s,3H).

Step 3: methyl2-((trifluoromethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate

To a solution of methyl5,6,8-tribromo-3-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-7-carboxylate(3.1 g, 5.8 mmol) in EtOH (100 mL) was added ammonium formate (3.1 g,49.2 mmol) and 10% palladium/carbon (620 mg, 0.58 mmol). The reactionmixture was heated at reflux for 30 min. The catalyst was removed viafiltration and washed with EtOH. The filtrate was concentrated todryness. The resulting residue was repartitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were washed with saturated aqueous NaCl, dried overMgSO₄, filtered and concentrated to dryness to provide methyl2-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylate(1.5 g, 88%). The crude material was used directly in next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.53 (m, 2H),7.02-6.88 (m, 1H), 4.50 (dd, J=6.0, 2.0 Hz, 1H), 4.34 (dd, J=11.7, 2.4Hz, 1H), 4.26-4.08 (m, 3H), 3.88 (s, 3H).

Step 4:2-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid

To a solution of methyl2-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylate(165 mg, 0.56 mmol) in MeOH (3 mL) was added NaOH (113 mg, 2.82 mmol) inwater (1 mL). The reaction mixture was stirred at rt for 72 h, dilutedwith H₂O, and acidified using 1 N HCl to pH ˜2. The resultingprecipitate was collected via vacuum filtration and washed with coldwater to provide2-(trifluoromethoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid (140 mg, 89.1%). ¹H NMR (400 MHz, CDCl₃) δ 7.67 (td, J=4.5, 2.0 Hz,2H), 7.04-6.88 (m, 1H), 4.52 (td, J=7.8, 2.4 Hz, 1H), 4.36 (dd, J=11.7,2.4 Hz, 1H), 4.28-4.07 (m, 3H).

4-(2-fluoro-2-methyl-propoxy)-3-methyl-benzoic acid Step 1: methyl4-(2-fluoro-2-methyl-propoxy)-3-methyl-benzoate

A solution of methyl 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoate(4.0 g, 16.8 mmol) was dissolved in DCM (40 mL) and treated withdeoxy-fluor (3.4 mL, 18.5 mmol) slowly while a water bath was used tokeep the reaction mixture near rt. The reaction mixture was allowed tostir at rt for 2 h, diluted with DCM (35 mL), and washed with water (75mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography: 80 gram silica gel column, 0-10% ethylacetate/hexane gradient over 30 min; providing methyl4-(2-fluoro-2-methyl-propoxy)-3-methyl-benzoate (2.5 g, 62%) as a clearcolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.90-7.83 (m, 2H), 6.80 (d,J=8.5 Hz, 1H), 3.99 (d, J=16.5 Hz, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.52(d, J=21.4 Hz, 6H). ESI-MS m/z calc. 240.1. found 241.4 (M+1)⁺;Retention time: 1.86 min (3 min run).

Step 2: 4-(2-fluoro-2-methyl-propoxy)-3-methyl-benzoic acid

To a solution of methyl 4-(2-fluoro-2-methyl-propoxy)-3-methyl-benzoate(2.5 g, 10.4 mmol) dissolved in methanol (2 mL) was added a solution ofsodium hydroxide (1.2 g, 31.1 mmol) in water (6 mL). The reactionmixture was allowed to stir at 55° C. for 30 min. The resulting clearsolution was concentrated under reduced pressure. The obtained whitesolid was redissolved in water (50 mL) and washed with ethyl acetate(1×50 mL). The aqueous layer was adjusted to pH 2 with the addition ofaqueous 1 N HCl solution, resulting in a cloudy white suspension. Themixture was extracted with ethyl acetate (2×75 mL) and the combinedorganics were dried over sodium sulfate, filtered and concentrated underreduced pressure to provide4-(2-fluoro-2-methyl-propoxy)-3-methyl-benzoic acid (1.9 g, 81%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J=8.5, 2.2 Hz, 1H),7.92 (d, J=1.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 4.01 (d, J=16.5 Hz, 2H),2.30 (s, 3H), 1.54 (d, J=21.4 Hz, 6H). ESI-MS m/z calc. 226.1. found453.3 (M+1)+; Retention time: 1.53 min (3 min run).

3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid Step 1: methyl3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoate

A 100 mL RB flask was fitted with a teflon stirrer bar, a magneticstirrer, a cooling bath and a nitrogen inlet/outlet. The vessel wascharged under a nitrogen atmosphere with 60% sodium hydride (1.1 g, 26.7mmol) in mineral oil and cooled to 0° C. with an ice bath. The vesselwas then charged with N,N-dimethylformamide (35 ml) via syringe andstirring was commenced. The vessel was then charged with methyl4-hydroxy-3-methoxy-benzoate (4.9 g, 26.7 mmol) as a solid in 4 equalportions over 20 min resulting in slight foaming. The reaction mixturewas stirred for 20 min and then treated with 2-(trifluoromethoxy)ethyltrifluoromethanesulfonate (14.0 g, 26.7 mmol) neat via canula over 10min. The cooling bath was removed and the reaction mixture was continuedto stir and allowed to warm to rt. The reaction mixture was heated to40° C. for 30 min, After cooling to rt the reaction mixture was pouredonto crushed ice (150 g). The mixture was diluted with water (150 ml)and then transferred to a separatory funnel and partitioned with ethylacetate (250 ml). The organic was removed and the aqueous layer wasextracted with ethyl acetate (2×100 ml). The combined organics werewashed with 0.1 M NaOH aqueous solution (2×150 ml), saturated aqueoussodium chloride (4×150 ml), dried over sodium sulfate (250 g), andfiltered through a glass frit Buchner funnel. The filtrate wasconcentrated under reduced pressure. Purification by flash columnchromatography (SiO₂-220 g, 0-20% ethyl acetate-hexanes) afforded methyl3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoate (7.5 g, 95%). ¹H NMR(400 MHz, CDCl₃) δ 7.68 (dd, J=8.4, 2.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H),6.92 (d, J=8.4 Hz, 1H), 4.41-4.29 (m, J=8.3, 5.3, 2.7 Hz, 4H), 3.94 (s,3H), 3.92 (s, 3H).

The following compounds were prepared using the procedure reportedabove.

Product Precursor methyl 3-methoxy-4-[2- Methyl 4-hydroxy-3-methoxy-(trifluoromethoxy)ethoxy]benzoate benzoate methyl 3-methyl-4-[2- Methyl4-hydroxy-3-methyl-benzoate (trifluoromethoxy)ethoxy]benzoate methyl3-chloro-4-(2- Methyl 4-hydroxy-3-chloro-benzoate(trifluoromethoxy)ethoxy)benzoate methyl 3-fluoro-4-[2- Methyl4-hydroxy-3-fluoro-benzoate (trifluoromethoxy)ethoxy]benzoate methyl3-chloro-5-methoxy-4-(2- methyl 3-chloro-4-hydroxy-5-(trifluoromethoxy)ethoxy)benzoate methoxybenzoate

Step 2: 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid

A solution of methyl 3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoate(5.1 g, 17.5 mmol) in methyl alcohol (24 mL) was treated with aqueoussodium hydroxide (96.1 mL of 1 M, 96.1 mmol). The reaction mixture washeated to 50° C. for 1 h (reaction mixture became homogeneous duringthis time). After cooling to rt the methyl alcohol was removed underreduced pressure. The remaining aqueous mixture was treated with cold 37wt. % HCl until pH-1 which resulted in the formation of a precipitate.The solid was collected by vacuum filtration in a glass frit Buchnerfunnel and washed with water (2×150 ml). The material was further driedunder vacuum to provide 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoicacid (4.3 g, 88%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 12.73 (s,1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.08 (d,J=8.5 Hz, 1H), 4.43 (dd, J=5.3, 3.0 Hz, 2H), 4.38-4.24 (m, 2H), 3.82 (s,3H). ESI-MS m/z calc. 280.1. found 281.1 (M+1)⁺; Retention time: 0.52min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor 3-methoxy-4-(2- methyl 3-methoxy-4-[2-(trifluoromethoxy)ethoxy)benzoic (trifluoromethoxy)ethoxy]benzoate acid3-methyl-4-(2- methyl 3-methyl-4-[2- (trifluoromethoxy)ethoxy)benzoic(trifluoromethoxy)ethoxy]benzoate acid 1 3-chloro-4-(2- methyl3-chloro-4-(2- (trifluoromethoxy)ethoxy)benzoic(trifluoromethoxy)ethoxy)benzoate acid 3-fluoro-4-[2- methyl3-fluoro-4-[2- (trifluoromethoxy)ethoxy]benzoic(trifluoromethoxy)ethoxy]benzoate acid 3-chloro-5-methoxy-4-(2- methyl3-chloro-5-methoxy-4-(2- (trifluoromethoxy)ethoxy)benzoic(trifluoromethoxy)ethoxy)benzoate acid

3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid Step 1: methyl3-methyl-4-(2,2,2-trifluoroethoxy)benzoate

To a solution of methyl 4-hydroxy-3-methyl-benzoate (1.6 g, 10 mmol) inDMF (20 mL) was added cesium carbonate (2.7 g, 20.0 mmol) and2-bromo-1,1,1-trifluoro-ethane (1.8 mL, 20.0 mmol). The reaction mixturewas heated at 80° C. overnight and was recharged with2-bromo-1,1,1-trifluoro-ethane (1 mL, 11 mmol) and heated at 80° C.overnight. The reaction mixture was recharged again with2-bromo-1,1,1-trifluoro-ethane (2 mL, 22 mmol) and heated at 80° C. for6 h. The reaction mixture was quenched and partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetate(3×). The combined organic layers were washed with water (3×), 1Naqueous NaOH, saturated aqueous NaCl, dried over MgSO₄, filtered andconcentrated to dryness. The crude material was used directly in nextstep without further purification. ESI-MS m/z calc. 248.2. found 249.3(M+1)⁺; Retention time: 2.02 min (3 min run).

Step 2: 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid

To a suspension of methyl 3-methyl-4-(2,2,2-trifluoroethoxy)benzoate(1.7 g, 6.8 mmol) in MeOH (20 mL) and water (10 mL) was added NaOH (1.4g, 34.2 mmol). The reaction mixture was stirred at rt overnight, turnedclear, and concentrated (removing MeOH) under reduced pressure. Theresidual solution was diluted with water and acidified with 1 N HCl. Theresulting precipitate was collected via filtration, washed with waterand dried to provide 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (1.6g, 100%) as an off-white solid. ESI-MS m/z calc. 234.2. found 235.2(M+1)⁺; Retention time: 1.73 min (3 min run).

[(3aR,7aR)-7a-[3-(2-tert-butoxyethoxy)-2-pyridyl]-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[4-(2-tert-butoxyethoxy)-3-chloro-phenyl]methanoneStep 1:[(3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone

A 20 mL vial was charged with(3aR,7aR)-7a-(3-fluoro-2-pyridyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine(258 mg, 1.15 mmol), 3-chloro-4-fluoro-benzoic acid (201 mg, 1.15 mmol),HATU (481 mg, 1.27 mmol) and DMF (5 mL). To the resulting solution wasadded triethylamine (640 μL, 4.6 mmol) and the reaction mixture wasstirred at rt for 2 h. Water (50 mL) was added, and the resultingmixture was extracted with DCM (3×25 mL). The combined extracts werewashed with water (25 mL), dried over sodium sulfate and concentratedunder reduced pressure. The crude residue was purified by flashchromatography on silica gel (12 g column) using a gradient of AcOEt (0to 100%) in hexanes over 12 min affording[(3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone(365 mg, 78%) as a viscous colorless oil. ESI-MS m/z calc. 380.1. found381.0 (M+1)⁺; Retention time: 1.09 min (3 min run).

Step 2:[(3aR,7aR)-7a-[3-(2-tert-butoxyethoxy)-2-pyridyl]-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[4-(2-tert-butoxyethoxy)-3-chloro-phenyl]methanone

In a vial, 2-tert-butoxyethanol (155 mg, 1.31 mmol) was dissolved in DMF(500 NaH (53 mg, 1.3 mmol) (60% oil dispersion) was added in smallportions and the suspension was stirred at rt for 25 min.[(3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone(50 mg, 0.13 mmol) as a solution in DMF (100 μL) was added and thereaction mixture was stirred at 80° C. for 1 h. The reaction mixture wasquenched by the addition of water. The resultant mixture was extractedwith DCM (3×). The combined extracts were dried over sodium sulfate andthe volatiles were removed under reduced pressure. The crude product waspurified by reverse phase HPLC (HCl as a modifier) providing[(3aR,7aR)-7a-[3-(2-tert-butoxyethoxy)-2-pyridyl]-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[4-(2-tert-butoxyethoxy)-3-chloro-phenyl]methanone(38 mg, 47%) as a colorless solid. ESI-MS m/z calc. 576.3. found 577.0(M+1)⁺; Retention time: 1.48 min (3 min run).

3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)benzoic acid Step 1:Methyl 4-hydroxy-3-(trifluoromethyl)benzoate

4-hydroxy-3-(trifluoromethyl)benzoic acid (4.9 g, 23.7 mmol) wasdissolved in methanol (15 mL) and DMF (18 μL, 0.24 mmol), thionylchloride (5.2 mL, 71.0 mmol) was added dropwise (over a period of 10min) to the reaction mixture, and it was allowed to stir for 18 h at rt.Volatiles were then removed under reduced pressure. The remaining solidwas partitioned between ethyl acetate (50 mL) and saturated aqueoussodium bicarbonate (50 mL). The aqueous layer was further extracted withethyl acetate (2×50 mL). All organic layers were combined, dried oversodium sulfate, filtered and concentrated under reduced pressure toprovide methyl 4-hydroxy-3-(trifluoromethyl)benzoate (4.9 g, 93%) as anoff-white solid. ¹H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 8.00-8.10 (m,2H), 7.20-7.07 (m, 1H), 3.83 (s, 3H). ESI-MS m/z calc. 220.0. found221.0 (M+1)⁺; Retention time: 1.41 min (3 min run).

Step 2: methyl 3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)benzoate

In a vial, methyl 4-hydroxy-3-(trifluoromethyl)benzoate (1.04 g, 4.73mmol) was dissolved in DMF (2 mL). Cesium carbonate (4.6 g, 14.2 mmol)was added followed by 3-bromo-1,1,1-trifluoro-propane (760 μl, 7.1mmol). The vial was tightly capped and the heterogenous mixture wasstirred at 80° C. for 1 h. The resulting thick slurry was diluted withDMF (5 mL) and treated with additional 3-bromo-1,1,1-trifluoro-propane(760 μL, 7.1 mmol). The reaction mixture was stirred at 80° C. for 15 hand treated with additional 3-bromo-1,1,1-trifluoro-propane (1.5 mL,14.2 mmol). The reaction mixture was stirred at 80° C. under nitrogenatmosphere for 4 days and treated with additional3-bromo-1,1,1-trifluoro-propane (1.5 mL, 14.2 mmol). The reactionmixture was heated at 80° C. for 24 h and was cooled and filtered. Thesolids were washed with methanol. The filtrate was concentrated underreduced pressure. Water (50 mL) and ethyl acetate (50 mL) were added andseparated. The aqueous phase was further extracted with ethyl acetate(50 mL). The combined extracts were washed with saturated aqueous NaCl,dried over sodium sulfate, filtered, and the volatiles were removedunder reduced pressure. Purification by flash chromatography on silicagel (24 g column) using a gradient of AcOEt (0 to 50% over 20 min) inhexanes provided methyl3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)benzoate (387 mg, 26%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=2.0 Hz, 1H), 8.21(dd, J=8.7, 2.1 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 4.34 (t, J=6.5 Hz, 2H),3.92 (s, 3H), 2.72 (qt, J=10.4, 6.5 Hz, 2H). ESI-MS m/z calc. 316.1.found 317.0 (M+1)⁺;

Retention time: 1.88 min (3 min run).

Step 3: 3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)benzoic acid

A solution of methyl3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)benzoate (380 mg, 1.20mmol) in methanol (2 mL) was treated with aqueous sodium hydroxide (600μl of 6 M, 3.6 mmol). The thick suspension was stirred at 60° C. andbecame a clear solution after 5 min. After stirring at 60° C. for 1.5 hthe reaction mixture was diluted with water (25 mL) and was acidifiedwith 6N HCl to pH=1. The resulting white precipitate was extracted withethyl acetate (2×25 mL). The combined extracts were dried over sodiumsulfate, filtered, and the volatiles were removed under reduced pressureto afford 3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)benzoic acid(342 mg, 94%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 13.18 (s, 1H),8.19 (dd, J=8.7, 2.1 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.43 (d, J=8.8 Hz,1H), 4.44 (t, J=5.6 Hz, 2H), 2.84 (ddq, J=16.8, 11.2, 5.7 Hz, 2H).ESI-MS m/z calc. 302.0. found 303.0 (M+1)⁺; Retention time: 1.62 min (3min run).

3-chloro-4-(2-fluoro-2-methyl-propoxy)benzoic acid Step 1: methyl3-chloro-4-(2-hydroxy-2-methylpropoxy)benzoate

A 500 ml 3 neck RB flask was fitted with a mechanical stirrer, a J-Kemtemperature probe/controller, an addition funnel, a water cooled refluxcondenser and a nitrogen inlet/outlet. The vessel was charged under anitrogen atmosphere with methyl 3-chloro-4-hydroxy-benzoate (10 g, 53.6mmol) and methyl alcohol (40 ml) which provided a clear pale yellowsolution. Stirring was commenced and the pot temperature was recorded at19° C. The vessel was then charged with potassium carbonate (30 g, 0.21mol) added as a solid in one portion which resulted in an exotherm to23° C. Note: The potassium carbonate was ground to a fine powder priorto use. The resulting suspension was continued to stir at rt for 15 minand then treated with 1-chloro-2-methyl-propan-2-ol (11.6 g, 0.11 mol)added neat dropwise via addition funnel over 10 min. The resultingreaction mixture/suspension was then heated to 70° C. and stirred for 20h. The reaction mixture was cooled to rt and diluted with ethyl acetate(250 ml). The mixture was filtered through a glass frit Buchner funnelwith a 10 mm layer of Celite. The filter cake was washed with ethylacetate (2×100 ml). The filtrate was transferred to a separatory funneland partitioned with 1 M aqueous NaOH (250 ml). The organic was removedand washed with 1 M aqueous NaOH (2×150 ml), saturated aqueous sodiumchloride (150 ml), dried over sodium sulfate (250 g) and filteredthrough a glass frit Buchner funnel. The filtrate was concentrated underreduced pressure to provide methyl3-chloro-4-(2-hydroxy-2-methylpropoxy)benzoate (9.0 g, 65%) as a clearpale yellow oil. The material was used without further purification inthe next synthetic step. ESI-MS m/z calc. 258.7. found 259.2 (M+1)⁺;Retention time: 1.46 min (3 min run).

Step 2: methyl 3-chloro-4-(2-fluoro-2-methyl-propoxy)benzoate

A solution of methyl 3-chloro-4-(2-hydroxy-2-methyl-propoxy)benzoate(6.2 g, 24.0 mmol) in DCM (60 mL) was treated slowly with2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-4-sulfanyl)ethanamine (4.9 mL,26.4 mmol) while a water bath was used to keep the reaction temperaturenear rt. The reaction mixture was allowed to stir at rt for 2 h. Thereaction mixture was quenched with the addition of ice-cold water (75mL) and diluted with DCM (50 mL). The phases were separated and theorganic phase was washed with saturated aqueous NaCl (2×75 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure.Purification by silica gel column chromatography: 40 gram silica gelcolumn, 0-10% ethyl acetate/hexane gradient over 30 min provided methyl3-chloro-4-(2-fluoro-2-methyl-propoxy)benzoate (2.4 g, 39%) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=2.1 Hz, 1H), 7.92 (dd, J=8.6,2.1 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 4.06 (t, J=9.8 Hz, 2H), 3.90 (s,3H), 1.55 (d, J=21.5 Hz, 6H). ESI-MS m/z calc. 260.1. found 261.2(M+1)⁺; Retention time: 1.83 min (3 min run).

Step 3: 3-chloro-4-(2-fluoro-2-methyl-propoxy)benzoic acid

A solution of methyl 3-chloro-4-(2-fluoro-2-methyl-propoxy)benzoate (2.4g, 9.3 mmol) in methanol (5 mL) was treated with a solution of sodiumhydroxide (1.1 g, 28.0 mmol) in water (10 mL). The reaction mixture wasallowed to stir at 60° C. for 1.5 h. The resulting clear solution wasdiluted with ethyl acetate (75 mL) and mixed with aqueous 1 N HCl (75mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to provide3-chloro-4-(2-fluoro-2-methyl-propoxy)benzoic acid (2.1 g, 93%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J=2.1 Hz, 1H), 8.00 (dd,J=8.6, 2.1 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 4.07 (d, J=16.1 Hz, 2H),1.56 (d, J=21.5 Hz, 6H). ESI-MS m/z calc. 246.0. found 247.2 (M+1)⁺;Retention time: 1.5 min (3 min run).

Methyl 3-methoxy-4-(3,3,3-trifluoropropoxy)benzoic acid Step 1: methyl3-methoxy-4-(3,3,3-trifluoropropoxy)benzoate

A solution of 3,3,3-trifluoropropan-1-ol (1.2 g, 10.9 mmol) in1,4-dioxane (4.5 mL) was cooled to 0° C. To the mixture was added a 60%dispersion of sodium hydride in mineral oil (0.4 g, 10.9 mmol) portionwise. A great deal of foaming was observed. After completion of addition(20 min), the reaction mixture was allowed to stir at rt for 1 h. Thereaction mixture was treated a solution of methyl4-fluoro-3-methoxy-benzoate (1.0 g, 5.4 mmol) in 1,4-dioxane (2 mL) andwas stirred at rt for 12 h. The reaction mixture was diluted with EtOAc(75 mL) and washed with a pH 14 solution of NaOH. The aqueous layer wasacidified to pH 10 with the addition of 1 N HCl, and was extracted withEtOAc (1×75 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to afford a yellow oil.Purification by flash column chromatography (SiO₂-24 g, 0-30%EtOAc-hexanes) afforded methyl3-methoxy-4-(3,3,3-trifluoropropoxy)benzoate (0.6 g, 39.7%). ESI-MS m/zcalc. 278.2 found 279.2 (M+1)⁺; Retention time: 0.62 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor methyl 3-methoxy-4-(3,3,3- methyl4-fluoro-3-methoxy-benzoate trifluoropropoxy)benzoate methyl3-methoxy-4-((4,4,4- methyl 4-fluoro-3-methoxy-benzoatetrifluorobutan-2-yl)oxy)benzoate methyl 3-methoxy-4-((1,1,1- methyl4-fluoro-3-methoxy-benzoate trifluoropropan-2-yl)oxy)benzoate

Step 2: methyl 3-methoxy-4-(3,3,3-trifluoropropoxy)benzoic acid

Intermediate methyl 3-methoxy-4-(3,3,3-trifluoropropoxy)benzoate (480mg, 1.73 mmol) was dissolved in methanol (1.3 mL), and a solution ofsodium hydroxide (414 mg, 10.4 mmol) in water (2.6 mL) was added. Thereaction mixture was stirred at 60° C. for 1 h and was diluted withwater (50 mL) and acidified to pH 1 with the addition of 1 N HCl. Theresulting opaque white suspension was extracted with EtOAc (2×75 mL).The organic layers were combined, dried over sodium sulfate, filteredand concentrated to provide 3-methoxy-4-(3,3,3-trifluoropropoxy)benzoicacid (357 mg, 78.4%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 12.73(s, 1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.46 (d, J=1.9 Hz, 1H), 7.11 (d,J=8.5 Hz, 1H), 4.27 (t, J=6.0 Hz, 2H), 3.81 (s, 3H), 2.95-2.72 (m, 2H).ESI-MS m/z calc. 264.2. found 265.2 (M+1)⁺; Retention time: 0.5 min (3min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor 3-methoxy-4-(3,3,3- methyl 3-methoxy-4-(3,3,3-trifluoropropoxy)benzoic acid trifluoropropoxy)benzoate3-methoxy-4-((4,4,4-trifluorobutan-2- methyl 3-methoxy-4-((4,4,4-yl)oxy)benzoic acid trifluorobutan-2-yl)oxy)benzoate3-methoxy-4-((1,1,1-trifluoropropan- methyl 3-methoxy-4-((1,1,1-2-yl)oxy)benzoic acid trifluoropropan-2-yl)oxy)benzoate

3-fluoro-5-methoxy-4-(3,3,3-trifluoropropoxy)benzoic acid Step 1:3-fluoro-5-methoxy-4-(3,3,3-trifluoropropoxy)benzaldehyde

In a flask, 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.1 g, 6.2 mmol)was dissolved in DMF (7 mL). The mixture was treated with potassiumcarbonate (2.2 g, 15.9 mmol) and 3-bromo-1,1,1-trifluoro-propane (1.3mL, 12.5 mmol) and the reaction mixture was stirred under nitrogenatmosphere at 80° C. for 17 h. Additional3-bromo-1,1,1-trifluoro-propane (2.6 mL, 24.9 mmol) was added and thereaction mixture was stirred at 65° C. for 5 h (50% conversion). Anotherload of 3-bromo-1,1,1-trifluoro-propane (1.3 mL, 12.5 mmol) was addedand the reaction mixture was stirred at 65° C. for 2.5 d. The solidswere filtered and washed with methanol. The filtrate was concentratedunder reduced pressure and diluted with water (50 mL) and ethyl acetate(50 mL). The phases were separated after being mixed and the aqueousphase was extracted with ethyl acetate (50 mL). The combined extractswere washed with saturated aqueous NaCl (50 mL), dried over sodiumsulfate, filtered, and the volatiles were removed in vacuo. The crudesolid was purified by flash chromatography on silica gel (80 g column)using a gradient of AcOEt (0 to 50% over 40 min) in hexanes. The producteluted at 15-25% ethyl acetate (13-20 min) to provide3-fluoro-5-methoxy-4-(3,3,3-trifluoropropoxy)benzaldehyde (0.80 g, 48%)as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 9.86 (d, J=1.2 Hz, 1H),7.29-7.25 (m, 2H), 4.38 (td, J=6.8, 0.5 Hz, 2H), 3.95 (s, 3H), 2.66 (qt,J=10.6, 6.8 Hz, 2H). ESI-MS m/z calc. 266.1. found 267.0 (M+1)⁺;Retention time: 1.63 min (3 min run).

Step 2: 3-fluoro-5-methoxy-4-(3,3,3-trifluoropropoxy)benzoic acid

To a solution of3-fluoro-5-methoxy-4-(3,3,3-trifluoropropoxy)benzaldehyde (780 mg, 2.9mmol) in tBuOH (8 mL), water (5 mL) and acetonitrile (5 mL) was addedsodium dihydrogen phosphate (352 mg, 2.9 mmol), 2-methylbut-2-ene (1.0g, 14.7 mmol) and sodium chlorite (265 mg, 2.9 mmol). The reactionmixture was stirred at 25° C. for 21 h and additional sodium dihydrogenphosphate (563 mg, 4.7 mmol), 2-methyl-2-butene (1.5 mL, 14.6 mmol) andNaClO₂ (795 mg, 8.79 mmol) were added. The reaction mixture was stirredat rt for 7 h, acidified with 1N HCl, and diluted with ethyl acetate.The layers were separated and the aqueous layer was extracted with ethylacetate (2×). The organics were combined, dried with sodium sulfate,filtered and concentrated under reduced pressure to give a waxy solid.The compound was triturated in hexanes, filtered, and dried in a vacuumoven at 40° C. overnight to provide3-fluoro-5-methoxy-4-(3,3,3-trifluoropropoxy)benzoic acid (620 mg, 75%)as an off-white solid. ¹H NMR (400 MHz, DMSO) δ 12.97 (s, 1H), 7.43-7.40(m, 1H), 7.38 (dd, J=10.5, 1.9 Hz, 1H), 4.27 (t, J=5.9 Hz, 2H), 3.89 (s,3H), 2.75 (qt, J=11.4, 5.9 Hz, 2H). ESI-MS m/z calc. 282.1. found 283.0(M+1)⁺; Retention time: 1.49 min (3 min run).

5-chloro-6-[2-(trifluoromethoxy)ethoxy]pyridine-3-carboxylic acid

Step 1: A solution of methyl 5-chloro-6-oxo-1H-pyridine-3-carboxylate(1.0 g, 5.3 mmol) in DMF and cooled to 0° C. and treated slowly with 60%sodium hydride in mineral oil (213 mg, 5.3 mmol). After stirring at rtfor 10 min, 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (3.0 g,5.9 mmol) was added. The reaction mixture was allowed to stir overnightat rt. It was then diluted with ethyl acetate (75 mL) and washed withsaturated aqueous NaCl (2×75 mL). The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toprovide methyl5-chloro-6-[2-(trifluoromethoxy)ethoxy]pyridine-3-carboxylate (330 mg)as a brown solid which was dissolved in methanol (680 μL). The mixturewas treated with a solution of sodium hydroxide (1.3 mL of 2.5 M, 3.3mmol). The reaction mixture was allowed to stir at 60° C. for 1.5 h. Theresulting clear solution was diluted with ethyl acetate (75 mL) andmixed with aqueous 1 N HCl. The organic layer was separated, dried oversodium sulfate, filtered and concentrated under reduced pressure toprovide 5-chloro-6-[2-(trifluoromethoxy)ethoxy]pyridine-3-carboxylicacid (300 mg, 95.4%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 13.32(s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 4.78-4.58 (m,2H), 4.48 (dd, J=5.1, 3.4 Hz, 2H). ESI-MS m/z calc. 285.0. found 286.03(M+1)⁺; Retention time: 1.55 min (3 min run).

5-[(3,3-difluorocyclobutyl)methoxy]-6-methoxy-pyridine-2-carboxylic acidStep 1: methyl6-chloro-5-[(3,3-difluorocyclobutyl)methoxy]pyridine-2-carboxylate

To methyl 6-chloro-5-hydroxy-pyridine-2-carboxylate (500 mg, 2.7 mmol)in dry DMF (4 mL) was added NaH (117 mg, 2.9 mmol) (60% dispersion inoil). The mixture was stirred at rt for 15 min before being treated with(3,3-difluorocyclobutyl)methyl methanesulfonate (865 mg, 4.32 mmol). Theresulting reaction mixture was stirred at 90° C. for 5 h. The reactionmixture was cooled down to rt overnight. Water was added and theresulting beige precipitate was filtered and washed with water. The wetsolid was dissolved in DCM, dried over sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure and subjected to flashchromatography on silica gel (24 g column) using a gradient of AcOEt (0to 60%) in hexanes over 25 min affording methyl6-chloro-5-[(3,3-difluorocyclobutyl)methoxy]pyridine-2-carboxylate (384mg, 49.4%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.4Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 4.15 (d, J=5.3 Hz, 2H), 3.98 (s, 3H),2.86-2.68 (m, 3H), 2.68-2.52 (m, 2H). ESI-MS m/z calc. 291.0. found292.0 (M+1)⁺; Retention time: 1.51 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor methyl 6-chloro-5-[(3,3- methyl 6-chloro-5-hydroxy-difluorocyclobutyl)methoxy]pyridine-2- pyridine-2-carboxylatecarboxylate methyl 6-chloro-5-[[1- methyl 6-chloro-5-hydroxy-(trifluoromethyl)cyclopropyl]methoxy]- pyridine-2-carboxylatepyridine-2-carboxylate methyl 6-chloro-5- methyl 6-chloro-5-hydroxy-(cyclobutylmethoxy)pyridine-2-carboxylate pyridine-2-carboxylate

Step 2:5-[(3,3-difluorocyclobutyl)methoxy]-6-methoxy-pyridine-2-carboxylic acid

A microwave vessel was charged with methyl6-chloro-5-[(3,3-difluorocyclobutyl)methoxy]pyridine-2-carboxylate (300mg, 1.03 mmol), dioxane (4 mL), sodium methoxide (1.4 mL of 25% w/w, 6.2mmol) and water (61 μL, 3.40 mmol). The reaction mixture was stirredunder microwave irradiation at 110° C. for 30 min. The resultingreaction mixture was concentrated under reduced pressure. The remainingwhite solid was redissolved in water (50 mL) and was washed with ethylacetate (1×50 mL). The aqueous layer was acidified to pH 1 with theaddition of 6 N HCl solution and extracted with ethyl acetate (2×75 mL).The organic layers were combined, dried over sodium sulfate, filteredand concentrated under reduced pressure affording5-[(3,3-difluorocyclobutyl)methoxy]-6-methoxy-pyridine-2-carboxylic acid(263 mg, 84.6%) as a colorless viscous oil that solidified uponstanding. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J=8.0 Hz, 1H), 7.18 (d,J=8.0 Hz, 1H), 4.12 (d, J=5.8 Hz, 2H), 4.06 (s, 3H), 2.91-2.61 (m, 3H),2.59-2.42 (m, 2H). ESI-MS m/z calc. 273.1. found 274.0 (M+1)⁺; Retentiontime: 1.29 min (3 min run

The following compounds were prepared using the procedure reportedabove.

Product Precursor 5-[(3,3-difluorocyclobutyl)methoxy]-6- methyl6-chloro-5-[(3,3- methoxy-pyridine-2-carboxylic aciddifluorocyclobutyl)methoxy]- pyridine-2-carboxylate 5-[[1- methyl6-chloro-5-[[1- (trifluoromethyl)cyclopropyl]methoxy]-(trifluoromethyl)cyclopropyl]- 6-methoxy-pyridine-2-carboxylic acidmethoxy]pyridine-2-carboxylate 5-(cyclobutylmethoxy)-6-methoxy- methyl6-chloro-5- pyridine-2-carboxylic acid (cyclobutylmethoxy)pyridine-2-carboxylate

6-methoxy-5-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-2-carboxylic acid

1,1,1-trifluoropropan-2-ol (43 μL, 0.47 mmol) was dissolved in1,4-dioxane (700 μL), and sodium hydride (38 mg, 0.94 mmol) (60 wt % inmineral oil) was added. The mixture was stirred at rt for 10 min before6-chloro-5-fluoro-pyridine-2-carboxylic acid (75 mg, 0.43 mmol) wasadded, and the reaction mixture was stirred at 70° C. overnight. Thereaction mixture was treated with sodium methoxide (555 μl of 25% w/v,2.56 mmol) (in methanol) and was stirred at 65° C. for 2 h. The reactionmixture was diluted with water (50 mL) and washed with ethyl acetate(1×75 mL). The aqueous layer was acidified to pH 3 with the addition of1 N HCl and extracted with DCM (3×75 mL). The final organic layers werecombined, dried over sodium sulfate, filtered, and concentrated underreduced pressure to provide6-methoxy-5-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-2-carboxylic acidas a slightly yellow oil that crystallized upon standing. ESI-MS m/zcalc. 265.1. found 266.3 (M+1)⁺; Retention time: 1.24 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor 6-methoxy-5-(2,2,2-trifluoro-1-methyl-6-chloro-5-fluoro-pyridine-2- ethoxy)pyridine-2-carboxylic acidcarboxylic acid 6-methoxy-5-(2,2,3,3- 6-chloro-5-fluoro-pyridine-2-tetrafluoropropoxy)picolinic acid carboxylic acid

(5-((6,6-difluorospiro[3.3]heptan-2-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone

A solution of[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(5-hydroxy-6-methoxy-2-pyridyl)methanone(85 mg, 0.23 mmol), (2,2-difluorospiro[3.3]heptan-6-yl)methylmethanesulfonate (109 mg, 0.45 mmol), and powdered potassium carbonate(110 mg, 0.79 mmol) in N,N-dimethylformamide (1.1 mL) was heated at 80°C. for 4 h. The reaction mixture was cooled to rt, filtered and purifiedby reverse phase HPLC (HCl modifier-1-100% ACN/H₂O) to afford(5-((6,6-difluorospiro[3.3]heptan-2-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(10 mg, 7.8%). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J=7.9 Hz, 1H), 7.36(td, J=8.0, 5.9 Hz, 1H), 7.20-7.12 (m, J=8.0 Hz, 2H), 7.09 (t, J=7.0 Hz,1H), 7.04-6.96 (m, 1H), 5.30 (d, J=31.5 Hz, 1H), 4.89 (d, J=29.1 Hz,1H), 4.52-4.22 (m, 1H), 4.13-4.04 (m, 2H), 4.03 (s, 3H), 4.02-3.91 (m,4H), 3.84-3.49 (m, 1H), 2.87-2.70 (m, 1H), 2.68-2.47 (m, 3H), 2.41-2.01(m, 6H). ESI-MS m/z calc. 518.2. found 519.2 (M+1)⁺; Retention time:1.621 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Mesylate [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-(2,2-difluorospiro[3.3]- tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-heptan-6-yl)methyl [5-[(2,2-difluorospiro[3.3]heptan-6- methanesulfonateyl)methoxy]-6-methoxy-2-pyridyl]methanone[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (2,2,3,3-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]- tetrafluorocyclobutyl)-[6-methoxy-5-[(2,2,3,3- methyl methanesulfonatetetrafluorocyclobutyl)methoxy]-2- pyridyl]methanone[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (3,3-difluorocyclopentyl)-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]- methyl methanesulfonate[5-[(3,3-difluorocyclopentyl)methoxy]-6- methoxy-2-pyridyl]methanone[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (2,2,3,3-tetrafluoro-1-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]- methyl-propyl)[6-methoxy-5-(2,2,3,3-tetrafluoro-1-methyl- methanesulfonatepropoxy)-2-pyridyl]methanone [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-(3,3-difluorocyclobutyl) tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-methanesulfonate [5-(3,3-difluorocyclobutoxy)-6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-cyclopent-3-en-1-ylmethyl tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-methanesulfonate [5-(cyclopent-3-en-1-ylmethoxy)-6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-cyclopent-3-en-1-yl tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-methanesulfonate (5-cyclopent-3-en-1-yloxy-6-methoxy-2-pyridyl)methanone [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-1-(3,3-difluorocyclobutyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-ethyl methanesulfonate [5-[1-(3,3-difluorocyclobutyl)ethoxy]-6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-2-(3,3-difluorocyclobutyl)- tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-ethyl methanesulfonate [5-[2-(3,3-difluorocyclobutyl)ethoxy]-6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-(3,3-difluoro-6- tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-bicyclo[3.1.0]hexanyl)- [5-[(3,3-difluoro-6- methyl methanesulfonatebicyclo[3.1.0]hexanyl)methoxy]-6-methoxy- 2-pyridyl]methanone

4-[2-(2,2-difluorocyclopropyl)ethoxy]-3-methoxy-benzoic acid Step 1:methyl 4-but-3-enoxy-3-methoxy-benzoate

In a vial, methyl 4-hydroxy-3-methoxy-benzoate (675 mg, 3.70 mmol) wasdissolved in DMF (4 mL) under a nitrogen atmosphere. The mixture wastreated with NaH (98 mg, 4.07 mmol) (60% dispersion in mineral oil) insmall portions and the reaction mixture was stirred at rt for 20 minbefore being treated dropwise with 4-bromobut-1-ene (1.0 g, 7.4 mmol).The vial was capped, covered with aluminium foil, and was stirred at 80°C. for 21 hours. The reaction mixture was cooled to rt and quenched bythe addition of water. The resulting mixture was extracted with ethylacetate (2×). The combined extracts were washed with water, dried oversodium sulfate, and concentrated under reduced pressure. Purification byflash chromatography on silica gel (40 g column) using a gradient ofAcOEt (0 to 40% over 25 min) in hexanes provided methyl4-but-3-enoxy-3-methoxy-benzoate (191 mg, 21.6%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 7.66 (dd, J=8.4, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz,1H), 6.89 (d, J=8.5 Hz, 1H), 5.91 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.19(dq, J=17.2, 1.6 Hz, 1H), 5.13 (ddd, J=10.2, 2.9, 1.2 Hz, 1H), 4.12 (t,J=7.1 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 2.63 (qt, J=7.0, 1.3 Hz, 2H).ESI-MS m/z calc. 236.1. found 237.0 (M+1)⁺; Retention time: 1.59 min (3min run).

Step 2: methyl 4-[2-(2,2-difluorocyclopropyl)ethoxy]-3-methoxy-benzoate

To a 15 mL pressure bottle charged with a magnetic stirbar was addedmethyl 4-but-3-enoxy-3-methoxy-benzoate (191 mg, 0.80 mmol), sodiumiodide (30 mg, 0.20 mmol) and anhydrous THF (1.2 mL) under a nitrogenatmosphere. To the mixture was added trimethyl-(trifluoromethyl)silane(414 μL, 2.80 mmol). The reaction vessel was sealed and heated to 65° C.for 21 h. The reaction mixture was cooled to rt and the volatiles wereremoved by blowing nitrogen over the vessel. The residue was redissolvedin dioxane (1.2 mL) before adding sodium iodide (30 mg, 0.20 mmol) andtrimethyl-(trifluoromethyl)silane (473 μL, 3.20 mmol) under nitrogen.The pressure vessel was sealed and stirred at 100° C. for 24 h. Thevessel was cooled to rt and the volatiles were removed by blowingnitrogen over the reaction mixture. The vessel was charged again withTHF (1.2 mL), sodium iodide (30 mg, 0.20 mmol),trimethyl-(trifluoromethyl)silane (414 μL, 2.80 mmol) and stirred at 65°C. for 24 h. The reaction mixture was cooled and the solvents wereremoved under reduced pressure. The residue was dissolved in DCM and theorganic phase was washed with water, 10% sodium sulfite, saturatedsodium bicarbonate and saturated aqueous NaCl. After drying over sodiumsulfate, the solvent was removed by evaporation. The crude material waspurified by flash chromatography on silica gel (24 g column) using agradient of AcOEt (0 to 40%) in hexanes over 25 min affording methyl4-[2-(2,2-difluorocyclopropyl)ethoxy]-3-methoxy-benzoate (147 mg, 63.3%)as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (dd, J=8.4, 2.0Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.21-4.10 (m,2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.15-1.91 (m, 2H), 1.76 (ddq, J=14.9,11.3, 7.5 Hz, 1H), 1.53-1.40 (m, 1H), 1.10-0.98 (m, 1H). ESI-MS m/zcalc. 286.1. found 287.0 (M+1)⁺; Retention time: 1.39 min (3 min run).

Step 3: 4-[2-(2,2-difluorocyclopropyl)ethoxy]-3-methoxy-benzoic acid

A solution of methyl4-[2-(2,2-difluorocyclopropyl)ethoxy]-3-methoxy-benzoate (144 mg, 0.50mmol) in methanol (1 mL) was treated with sodium hydroxide (250 μL, 1.50mmol) (6N aqueous solution) and the resulting reaction mixture wasstirred at 60° C. The reaction mixture was diluted with water (50 mL)and was acidified with 6N HCl to pH=1 inducing formation of a whiteprecipitate. The precipitate was filtered, washed with water and driedovernight under vacuum oven at 40° C. affording4-[2-(2,2-difluorocyclopropyl)ethoxy]-3-methoxy-benzoic acid (125 mg,87.8%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, J=8.4, 2.0Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 4.18 (t, J=6.1Hz, 2H), 3.93 (s, 3H), 2.04 (tdd, J=14.3, 13.0, 7.0 Hz, 2H), 1.77 (ddq,J=14.8, 11.2, 7.4 Hz, 1H), 1.54-1.40 (m, 1H), 1.11-0.94 (m, 1H). ESI-MSm/z calc. 272.1. found 273.0 (M+1)⁺; Retention time: 1.08 min.

(5-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanoneand(5-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone

To a solution of[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[5-(cyclopent-3-en-1-ylmethoxy)-6-methoxy-2-pyridyl]methanone(90 mg, 0.20 mmol) in THF (2 mL) was added sodium iodide (59 mg, 0.40mmol). The mixture was purged with nitrogen for 2 min andtrimethyl-(trifluoromethyl)silane (70 mg, 0.49 mmol) was added. Thereaction mixture was sealed and heated at 80° C. for 20 h. The reactionmixture was cooled to rt and partitioned between ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate (3×). Thecombined organic layers were washed with saturated aqueous NaCl, driedover MgSO₄, filtered and concentrated to dryness. The crude material waspurified by column chromatography to provide(5-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(3.2 mg, 3.0%). ESI-MS m/z calc. 504.5. found 505.3 (M+1)⁺; Retentiontime: 1.08 min. and(5-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(2.9 mg, 2.8%). ESI-MS m/z calc. 504.5. found 505.3 (M+1)⁺; Retentiontime: 2.01 min (3 min run).

[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[5-(2-cyclopropyl-2,2-difluoro-ethoxy)-6-methoxy-2-pyridyl]methanoneStep 1:2-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxy]-N-methoxy-N-methyl-acetamide

To a 25 mL round bottom flask was added[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(5-hydroxy-6-methoxy-2-pyridyl)methanone(75 mg, 0.20 mmol) and DMF (2 mL). The reaction mixture was cooled to 0°C. and sodium hydride (8 mg, 0.20 mmol) was added. After 5 min,2-chloro-N-methoxy-N-methyl-acetamide (28 mg, 0.20 mmol) was added andthe reaction mixture was heated at 45° C. overnight. The reactionmixture was filtered and purified via HPLC (1%-99%) ACN:H₂O with a 0.1%HCl modifier affording2-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxy]-N-methoxy-N-methyl-acetamide(28 mg, 28%) as a white solid. ESI-MS m/z calc. 475.2. found 476.3(M+1)+; Retention time: 1.73 min (3 min run).

Step 2:1-cyclopropyl-2-((6-(7a-(3-fluorophenyl)hexahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl)-2-methoxypyridin-3-yl)oxy)ethanone

To a 10 mL round bottom flask containing2-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxy]-N-methoxy-N-methyl-acetamide(23 mg, 0.05 mmol) was added THF (1 mL). The mixture was cooled to 0° C.and treated dropwise with cyclopropyl magnesium bromide (106 μL of 0.5 Min THF, 0.05 mmol). The reaction mixture was allowed to stir whilewarming to rt. The reaction mixture was quenched with saturated aqueousammonium chloride and extracted with ethyl acetate. The organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The crude reaction mixture was purified via reverse phase HPLC (1%-99%)ACN:H₂O. ESI-MS m/z calc. 475.2. found 476.3 (M+1)⁺; Retention time:1.73 min (3 min run).

Step 3:[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[5-(2-cyclopropyl-2,2-difluoro-ethoxy)-6-methoxy-2-pyridyl]methanone

To a 10 mL round bottom flask containing2-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxy]-1-cyclopropyl-ethanone(16 mg, 0.03 mmol) was added dichloromethane (1 mL). The reactionmixture was cooled to 0° C. and treated with ethanol (0.4 μL, 0.007mmol) followed by the dropwise addition of deoxy-fluor (16 L, 0.085mmol). The reaction mixture was allowed to stir overnight while warmingto rt. Deoxy-fluor (16 μL, 0.085 mmol) was added again and after 3 h thereaction mixture was diluted with dichloroethane (2 mL) and heated at50° C. oil bath overnight. The reaction mixture was quenched withsaturated aqueous ammonium chloride and extracted with dichloromethane.The dichloromethane was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified via reverse phase HPLC(1%-99%) ACN:H₂O with a 0.1% HCl modifier to afford[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[5-(2-cyclopropyl-2,2-difluoro-ethoxy)-6-methoxy-2-pyridyl]methanone(8.2 mg, 45.4%). ESI-MS m/z calc. 478.2. found 479.3 (M+1)⁺; Retentiontime: 1.82 min (3 min run).

4-[(3,3-difluorocyclobutyl)methylamino]-3-methoxy-benzoic acid

A solution of 4-amino-3-methoxy-benzoic acid (200 mg, 1.20 mmol) and3,3-difluorocyclobutanecarbaldehyde (144 mg, 1.20 mmol) in1,2-dichloroethane (4 mL) were treated with sodium triacetoxyborohydride (317 mg, 1.68 mmol) and acetic acid (68 μL, 1.20 mmol). Adrop of TFA was added and the heterogenous reaction mixture wasvigorously stirred at rt for 16 h. To the mixture was added 1N NaOH (50mL) and DCM (50 mL) and the two phases were separated. The aqueous phasewas acidified to pH=6 using 6N HCl and was extracted with DCM:methanol(10:1) (40 mL). The aqueous phase was further acidified to pH=1 and thenwas extracted with DCM:methanol (10:1) (2×30 mL). The combined organicextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude product purified by reverse phasepreparative HPLC using HCl as a modifier. Evaporation of the volatilesunder reduced pressure provided4-[(3,3-difluorocyclobutyl)methylamino]-3-methoxy-benzoic acid (17 mg,5.1%) as a white solid. ESI-MS m/z calc. 271.1. found 272.0 (M+1)⁺;Retention time: 1.3 min (3 min run).

4-[(3,3-difluorocyclobutyl)methoxy]-3-methoxy-benzoic acid Step 1:methyl 3-chloro-4-((3,3-difluorocyclobutyl)methoxy)benzoate

A 1 L flask equipped with a nitrogen inlet, a condenser and a magneticstirbar was charged with (3,3-difluorocyclobutyl)methyl methanesulfonate(19.7 g, 88.6 mmol) and anhydrous DMF (400 mL). The mixture was treatedwith methyl 4-hydroxy-3-methoxy-benzoate (16.1 g, 88.5 mmol) andpowdered K₂CO₃ (24.5 g, 177.1 mmol). The reaction mixture was heated at80° C. for 30 min. Once the bath reached this temperature, the reactionmixture turned into a very thick gel that rendered magnetic stirringalmost inoperative. The reaction mixture required intermittent manualstirring of the gel with a spatula for 3 h. Progressively, efficientstirring was restored and the reaction was stirred for an additionally 4h. The reaction mixture was cooled down to rt overnight and poured intoice-cold water under stirring (divided into 2×1.4 L). The resultingsuspensions were stirred at rt for 4 h and were filtered on the samebuchner filter. The combined white solid was washed with water (2×200mL) and partially dried by suction. The wet solid was dissolved in DCM(200 mL) and the residual water was separated by decantation. Theorganic layer was dried over sodium sulfate, filtered, and the solventsconcentrated under reduced pressure to afford a crude pink solid.Purification by flash chromatography on silica gel (330 g column) usinga gradient of AcOEt (0 to 70% over 30 min) in hexanes provided methyl3-chloro-4-((3,3-difluorocyclobutyl)methoxy)benzoate (22 g, 88% yield)as a white solid. ESI-MS m/z calc. 286.0. found 287.0 (M+1); Retentiontime: 1.57 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Benzoate Mesylate methyl 3-chloro-4-((3,3- methyl 3-chloro-4-(3,3- difluorocyclobutyl)methoxy)benzoate hydroxybenzoatedifluorocyclobutyl)methyl methanesulfonate methyl 3-chloro-4-[[1- methyl3-chloro-4- (1- (trifluoromethyl)cyclopropyl]- hydroxybenzoate(trifluoromethyl)cyclopropyl)methyl methoxy]benzoate methanesulfonatemethyl4-[(3,3- methyl 3-methoxy- (3,3-difluorocyclopentyldifluorocyclopentyl)methoxy]- 4-hydroxybenzoate methanesulfonate3-methoxy-benzoate methyl 4-[(3,3- methyl 3-methoxy- (3,3-difluorocyclobutyl)methoxyl]- 4-hydroxybenzoatedifluorocyclobutyl)methyl 3-methoxy-benzoate methanesulfonate methyl3-methoxy-4-[[1- methyl 3-methoxy- (1- (trifluoromethyl)cyclopropyl]-4-hydroxybenzoate (trifluoromethyl)cyclopropyl)methyl methoxy]benzoatemethanesulfonate methyl 3-methoxy-4- methyl 3-methoxy-2,2,3,3-tetrafluoropropoxy (2,2,3,3- 4-hydroxybenzoate methanesulfonatetetrafluoropropoxy)bbenzoate

Step 2: 4-[(3,3-difluorocyclobutyl)methoxy]-3-methoxy-benzoic acid

In a 500 mL round bottom flask equipped with a magnetic stirbar, methyl3-chloro-4-((3,3-difluorocyclobutyl)methoxy)benzoate (22 g, 77 mmol) wassuspended in MeOH (100 mL) and was stirred at 60° C. until all solidsdissolved. NaOH (30 mL of 6 M, 180.0 mmol) (6N aqueous) was added andthe mixture was stirred at 60° C. for 1 h. The reaction mixture wascooled to rt, transferred into a 1 L erlenmeyer flask and diluted withwater (500 mL). The solution was neutralized by dropwise addition ofaqueous 6N HCl (30 mL) over 20 min, until the solution reached pH=2.More water was added (200 mL). The resulting white precipitate wasfiltered, washed with water (3×100 mL) and dried under vacuum (40° C.)for 3 d affording 4-[(3,3-difluorocyclobutyl)methoxy]-3-methoxy-benzoicacid (20.8 g, 86%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd,J=8.4, 2.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.13(d, J=6.2 Hz, 2H), 3.92 (s, 3H), 2.90-2.63 (m, 3H), 2.63-2.34 (m, 2H).ESI-MS m/z calc. 272.1. found 273.0 (M+1)+; Retention time: 1.26 min (3min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor 3-chloro-4-[(3,3- methyl 3-chloro-4-((3,3-difluorocyclobutyl)methoxy]benzoic difluorocyclobutyl)methoxy)- acidbenzoate 3-chloro-4-[[1- methyl 3-chloro-4-[[1-(trifluoromethyl)cyclopropyl]methoxy]- (trifluoromethyl)cyclopropyl]-benzoic acid methoxy]benzoate 4-[(3,3-difluorocyclopentyl)methoxy]-3-methyl4-[(3,3- methoxy-benzoic acid difluorocyclopentyl)methoxy]-3-methoxy-benzoate 4-[(3,3-difluorocyclobutyl)methoxy]-3- methyl 4-[(3,3-methoxy-benzoic acid difluorocyclobutyl)methoxy]-3- methoxy-benzoate3-methoxy-4-[[1- methyl 3-methoxy-4-[[1- (trifluoromethyl)cyclopropyl]-(trifluoromethyl)cyclopropyl]- methoxy]benzoic acid methoxy]-benzoate3-methoxy-4-(2,2,3,3- methyl 3-methoxy-4-(2,2,3,3-tetrafluoropropoxy)benzoic acid tetrafluoropropoxy)bbenzoate

[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[4-[(3,3-difluorocyclobutyl)methyl-methyl-amino]-3-methoxy-phenyl]methanone

(4-(((3,3-difluorocyclobutyl)methyl)amino)-3-methoxyphenyl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(8.1 mg, 0.017 mmol) was dissolved in DMF (100 μL). K₂CO₃ (7.0 mg, 0.051mmol) and Met (5 μL, 0.08 mmol) were added and the reaction mixture wasstirred at rt for 3 days. The reaction mixture was diluted with water(50 uL) and DMF (850 uL), filtered and purified by preparative HPLCusing HCl as a modifier. The pure fraction were collected and thesolvents removed by evaporation under reduced pressure to afford[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[4-[(3,3-difluorocyclobutyl)methyl-methyl-amino]-3-methoxy-phenyl]methanone(2.5 mg, 30.0%) as a colorless film. ESI-MS m/z calc. 490.5. found 491.4(M+1)⁺; Retention time: 1.29 min (3 min run).

(5-((3,3-difluorobicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanoneStep 1:(5-((3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone

To a solution of [(3 aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-15tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(5-hydroxy-6-methoxy-2-pyridyl)methanone(400 mg, 1.07 mmol) in DMF (5 mL) was added potassium carbonate (221 mg,1.60 mmol) followed by the addition of(3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)methylmethanesulfonate (377 mg, 1.18 mmol). The mixture was heated at 80° C.overnight. The reaction mixture was recharged with(3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)methylmethanesulfonate (377 mg, 1.18 mmol) and heated at 140° C. overnight.After cooling to rt, the mixture was repartitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were washed with saturated aqueous NaCl (4×), dried overMgSO₄, filtered and concentrated to dryness. The crude material waspurified by column chromatography (20-30% EtOAc-Hex) to provide(5-((3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(220 mg, 34.4%). ESI-MS m/z calc. 598.3. found 599.5 (M+1)⁺; Retentiontime: 2.65 min (3 min run).

Step 2:((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)(5-((3-hydroxybicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)methanone

To a solution of(5-((3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(220 mg, 0.37 mmol) in THF (5 mL) was added tetrabutylammonium fluoride(108 μL, 0.37 mmol). The mixture was heated at 70° C. for 1 h. Thereaction mixture was stirred at 50° C. for 24 h and repartitionedbetween EtOAc and water. The aqueous layer was extracted with EtOAc(3×). The combined organic layers were washed with saturated aqueousNaCl, dried over MgSO₄, filtered, and concentrated to dryness. The crudematerial was purified by column chromatography (80-100% EtOAc-Hex) toprovide((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)(5-((3-hydroxybicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)methanone(105 mg, 56%). ESI-MS m/z calc. 484.2. found 485.5 (M+1)+; Retentiontime: 1.71 min (3 min run).

Step 3:6-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxymethyl]bicyclo[3.1.0]hexan-3-one

To a solution of ((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)(5-((3-hydroxybicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)methanone(90 mg, 0.19 mmol) in dichloromethane (10 mL) was added Dess Martinperiodinane (87 mg, 0.20 mmol). The reaction mixture was stirred at rtfor 30 min, diluted with DCM, washed with saturated aqueous Na₂S₂O₃(2×), saturated aqueous NaHCO₃, saturated aqueous NaCl, dried overMgSO₄, filtered and concentrated to dryness. The crude material waspurified by column chromatography to provide6-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxymethyl]bicyclo[3.1.0]hexan-3-one(72 mg, 80%) as a mixture of diastereomers. ¹H NMR (400 MHz, CDCl₃) δ7.44 (d, J=8.0 Hz, 1H), 7.36 (td, J=8.0, 5.9 Hz, 1H), 7.20-7.06 (m, 3H),7.07-6.95 (m, 1H), 5.37-5.21 (m, 1H), 4.89 (d, J=28.4 Hz, 1H), 4.40 (dt,J=28.2, 4.3 Hz, 1H), 4.12-3.90 (m, 8H), 3.82-3.52 (m, 1H), 2.65 (dd,J=20.8, 2.7 Hz, 2H), 2.37-2.08 (m, 4H), 1.67 (s, 2H), 1.10-0.90 (m, 1H).ESI-MS m/z calc. 482.2. found 483.7 (M+1)⁺; Retention time: 1.77 min (3min run).

Step 4:(5-((3,3-difluorobicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone

A solution of6-[[6-[(3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carbonyl]-2-methoxy-3-pyridyl]oxymethyl]bicyclo[3.1.0]hexan-3-one(23 mg, 0.05 mmol) in DCM (2 mL) and EtOH (0.6 μL, 0.010 mmol) waspurged with nitrogen for 5 min. Deoxy-fluor (26 mg, 0.12 mmol) was addedand the reaction mixture was heated at 50° C. for 30 min. The reactionmixture was recharged with deoxy-fluor (26 mg, 0.12 mmol) and heated at50° C. for 18 h. The reaction was recharged with deoxy-fluor (26 mg,0.12 mmol) and heated at 50° C. for 60 h. The reaction mixture wasquenched with saturated aqueous ammonium chloride and extracted withDCM. The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. Purification by columnchromatography (40-60% EtOAc-Hex) afforded(5-((3,3-difluorobicyclo[3.1.0]hexan-6-yl)methoxy)-6-methoxypyridin-2-yl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone(5.5 mg, 20.6%). ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=8.0 Hz, 1H), 7.36(td, J=8.0, 6.0 Hz, 1H), 7.15 (d, J=7.2 Hz, 2H), 7.13-7.06 (m, 1H), 7.00(dd, J=9.7, 7.4 Hz, 1H), 5.30 (t, J=15.3 Hz, 1H), 4.89 (d, J=28.6 Hz,1H), 4.38 (dd, J=18.1, 14.0 Hz, 1H), 4.09-3.85 (m, 8H), 3.79-3.55 (m,1H), 2.51-2.08 (m, 6H), 1.47 (s, 2H), 1.24 (dt, J=11.4, 6.4 Hz, 1H).ESI-MS m/z calc. 504.2. found 505.5 (M+1)⁺; Retention time: 1.84 min (3min run).

[(3aR,7aR)-7a-(3,5-difluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone

A 20 mL vial was charged with(3aR,7aR)-7a-(3,5-difluorophenyl)-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridine(215 mg, 0.89 mmol), 3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoicacid (250 mg, 0.89 mmol) and HATU (372.8 mg, 0.98 mmol). Anhydrous DMF(3.5 mL) was added and the mixture was stirred until all solidsdissolved. Triethyl amine (497 μL, 3.56 mmol) was added and the mixturewas stirred at rt for 2.5 h at which time LCMS indicated completion ofthe reaction. Water and saturated aqueous NaCl were added. The gummymaterial that formed was separated from the aqueous phase and wasdissolved in DCM (50 mL). The organic phase was dried over sodiumsulfate and the solvent concentrated under reduced pressure. The productwas purified by flash chromatography on silica gel (24 g column) using agradient of AcOEt (0 to 100% over 15 min) in hexanes. The product elutedat 65-85% ethyl acetate (10-13 min run). The pure fractions werecollected and the solvents removed under reduced pressure.[(3aR,7aR)-7a-(3,5-difluorophenyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone(268 mg, 59.4%) was isolated as a solid off-white foam. ¹H NMR (400 MHz,CDCl₃) δ 7.11 (broad s, 1H), 7.06 (dd, J=8.2, 1.9 Hz, 1H), 6.96-6.87 (m,3H), 6.76 (tt, J=8.7, 2.3 Hz, 1H), 5.31 (s, 1H), 4.85 (s, 1H), 4.42-4.25(m, 4H), 4.2-4.0 (broad d, 2H), 3.90 (s, 3H), 3.72 (broad s, 3H),2.32-1.90 (broad m, 2H). ESI-MS m/z calc. 503.1. found 504.0 (M+1)+;Retention time: 1.91 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Acid Amine (4-isopropoxy-3-methyl- 4-isopropoxy-3- 6-phenyl-3-phenyl)-(6-phenyl-3- methyl-benzoic azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- acid yl)methanone [3-methoxy-4-[2-3-methoxy-4-[2- 6-phenyl-3- (trifluoromethoxy)ethoxy]phenyl]-(trifluoromethoxy)ethoxy]benzoic azabicyclo[4.1.0]heptan (6-phenyl-3-acid azabicyclo[4.1.0]heptane-3- yl)methanone (4-isopentyloxy-3-methoxy-4-isopentyloxy-3- 6-phenyl-3- phenyl)-(6-phenyl-3- methoxy-benzoicazabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3- acid yl)methanone[4-(1-hydroxy-1-methyl- 4-(1-hydroxy-1- 6-phenyl-3-ethyl)-3-methoxy-phenyl]-(6- methyl-ethyl)-3- azabicyclo[4.1.0]heptanephenyl-3- methoxy-benzoic azabicyclo[4.1.0]heptan-3- acid yl)methanone[3-methoxy-4- 3-methoxy-4- 6-phenyl-3- (tetrahydrofuran-2-(tetrahydrofuran-2- azabicyclo[4.1.0]heptaneylmethoxy)phenyl]-(6-phenyl- ylmethoxy)benzoic3-azabicyclo[4.1.0]heptan-3- acid yl)methanone [6-methoxy-5-[2-6-methoxy-5-[2- 6-phenyl-3- (trifluoromethoxy)ethoxy]-2-(trifluoromethoxy)ethoxy]pyridine- azabicyclo[4.1.0]heptanepyridyl]-(6-phenyl-3- 2- azabicyclo[4.1.0]heptan-3- carboxylic acidyl)methanone (5-isopropoxy-6-methyl-2- 5-isopropoxy-6- 6-phenyl-3-pyridyl)-(6-phenyl-3- methyl-pyridine-2- azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- carboxylic acid yl)methanone[5-(2-fluoro-2-methyl- 5-(2-fluoro-2- 6-phenyl-3- propoxy)-6-methoxy-2-methyl-propoxy)-6- azabicyclo[4.1.0]heptane pyridyl]-(6-phenyl-3-methoxy-pyridine- azabicyclo[4.1.0]heptan-3- 2-carboxylic acidyl)methanone [4-(2-fluoro-2-methyl- 4-(2-fluoro-2- 6-phenyl-3-propoxy)-3-methoxy-phenyl]- methyl-propoxy)-3- azabicyclo[4.1.0]heptane(6-phenyl-3- methoxy-benzoic azabicyclo[4.1.0]heptan-3- acidyl)methanone [4-(2-hydroxy-2-methyl- 4-(2-hydroxy-2- 6-phenyl-3-propoxy)-3-methyl-phenyl]- methyl-propoxy)-3- azabicyclo[4.1.0]heptane(6-phenyl-3- methyl-benzoic azabicyclo[4.1.0]heptan-3- acid yl)methanone[4-(1-hydroxy-1-methyl- 4-(1-hydroxy-1- 6-phenyl-3-ethyl)phenyl]-(6-phenyl-3- methyl- azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- ethyl)benzoic acid yl)methanone[3-fluoro-4-(1-hydroxy-1- 3-fluoro-4-(1- 6-phenyl-3-methyl-ethyl)phenyl]-(6- hydroxy-1-methyl- azabicyclo[4.1.0]heptanephenyl-3- ethyl)benzoic acid azabicyclo[4.1.0]heptan-3- yl)methanone[3-methoxy-4-(3,3,3- 3-methoxy-4- 6-phenyl-3-trifluoropropoxymethyl)phenyl]- (3,3,3- azabicyclo[4.1.0]heptane(6-phenyl-3- trifluoropropoxymethyl)benzoic azabicyclo[4.1.0]heptan-3-acid yl)methanone [4-(1-hydroxy-1-methyl- 4-(1-hydroxy-1- 6-phenyl-3-ethyl)-3-methyl-phenyl]-(6- methyl-ethyl)-3- azabicyclo[4.1.0]heptanephenyl-3- methyl-benzoic azabicyclo[4.1.0]heptan-3- acid yl)methanone(6-isopropoxy-3-pyridyl)-(6- 6- 6-phenyl-3- phenyl-3-isopropoxypyridine- azabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3-3-carboxylic acid yl)methanone [6-methyl-5-[2- 6-methyl-5-[2-6-phenyl-3- (trifluoromethoxy)ethoxy]-2-(trifluoromethoxy)ethoxy]pyridine- azabicyclo[4.1.0]heptanepyridyl]-(6-phenyl-3- 2- azabicyclo[4.1.0]heptan-3- carboxylic acidyl)methanone (3-fluoro-2-methoxy-phenyl)- 3-fluoro-2- 6-phenyl-3-(6-phenyl-3- methoxy-benzoic azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- acid yl)methanone 2,3-dihydrobenzofuran-7-yl-2,3- 6-phenyl-3- (6-phenyl-3- dihydrobenzofuran-azabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3- 7-carboxylic acidyl)methanone (6-phenyl-3- quinoline-8- 6-phenyl-3-azabicyclo[4.1.0]heptan-3-yl)- carboxylic acid azabicyclo[4.1.0]heptane(8-quinolyl)methanone [4-(2-hydroxy-2-methyl- 4-(2-hydroxy-2-6-phenyl-3- propoxy)-3-methoxy-phenyl]- methyl-propoxy)-3-azabicyclo[4.1.0]heptane (6-phenyl-3- methoxy-benzoicazabicyclo[4.1.0]heptan-3- acid yl)methanone 2-isopropoxy-5-(6-phenyl-3-3-cyano-4- 6-phenyl-3- azabicyclo[4.1.0]heptane-3- isopropoxy-benzoicazabicyclo[4.1.0]heptane carbonyl)benzonitrile acid(3-fluoro-4-isopropoxy- 3-fluoro-4- 6-phenyl-3- phenyl)-(6-phenyl-3-isopropoxy-benzoic azabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3-acid yl)methanone (6-isopropoxy-5-methyl-3- 6-isopropoxy-5- 6-phenyl-3-pyridyl)-(6-phenyl-3- methyl-pyridine-3- azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- carboxylic acid yl)methanone [4-(1- 4-(1-6-phenyl-3- hydroxycyclobutyl)phenyl]- hydroxycyclobutyl)benzoicazabicyclo[4.1.0]heptane (6-phenyl-3- acid azabicyclo[4.1.0]heptan-3-yl)methanone [3-fluoro-4-(2-hydroxy-2- 3-fluoro-4-(2- 6-phenyl-3-methyl-propyl)phenyl]-(6- hydroxy-2-methyl- azabicyclo[4.1.0]heptanephenyl-3- propyl)benzoic acid azabicyclo[4.1.0]heptan-3- yl)methanone(4-isopropoxy-2-methoxy- 4-isopropoxy-2- 6-phenyl-3-phenyl)-(6-phenyl-3- methoxy-benzoic azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- acid yl)methanoneN-cyclopropyl-4-(6-phenyl-3- 4- 6-phenyl-3- azabicyclo[4.1.0]heptane-3-(cyclopropylsulfamoyl)benzoic azabicyclo[4.1.0]heptanecarbonyl)benzenesulfonamide acid (4-ethylsulfonyl-3-methyl-4-ethylsulfonyl-3- 6-phenyl-3- phenyl)-(6-phenyl-3- methyl-benzoicazabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3- acid yl)methanone(2-fluoro-4-isopropoxy- 2-fluoro-4- 6-phenyl-3- phenyl)-(6-phenyl-3-isopropoxy-benzoic azabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3-acid yl)methanone [3-methoxy-4-(2,2,2- 3-methoxy-4- 6-phenyl-3-trifluoroethoxymethyl)phenyl]- (2,2,2- azabicyclo[4.1.0]heptane(6-phenyl-3- trifluoroethoxymethyl)benzoic azabicyclo[4.1.0]heptan-3-acid yl)methanone (5-methoxy-6-methyl-2- 5-methoxy-6- 6-phenyl-3-pyridyl)-(6-phenyl-3- methyl-pyridine-2- azabicyclo[4.1.0]heptaneazabicyclo[4.1.0]heptan-3- carboxylic acid yl)methanone(5-isobutoxy-2-pyridyl)-(6- 5- 6-phenyl-3- phenyl-3- isobutoxypyridine-azabicyclo[4.1.0]heptane azabicyclo[4.1.0]heptan-3- 2-carboxylic acidyl)methanone [5-(2-hydroxy-2-methyl- 5-(2-hydroxy-2- 6-phenyl-3-propoxy)-6-methoxy-2- methyl-propoxy)-6- azabicyclo[4.1.0]heptanepyridyl]-(6-phenyl-3- methoxy-pyridine- azabicyclo[4.1.0]heptan-3-2-carboxylic acid yl)methanone (4-isopropoxy-3-methyl- 4-isopropoxy-3-6-phenyl-7-oxa-3- phenyl)-(6-phenyl-7-oxa-3- methyl-benzoicazabicyclo[4.2.0]octane azabicyclo[4.2.0]octan-3- acid yl)methanone(5-isopropoxy-6-methyl-2- 5-isopropoxy-6- 6-phenyl-7-oxa-3-pyridyl)-(6-phenyl-7-oxa-3- methyl-pyridine-2- azabicyclo[4.2.0]octaneazabicyclo[4.2.0]octan-3- carboxylic acid yl)methanone [3-methoxy-4-[2-3-methoxy-4-[2- 6-phenyl-7-oxa-3- (trifluoromethoxy)ethoxy]phenyl]-(trifluoromethoxy)ethoxy]benzoic azabicyclo[4.2.0]octane(6-phenyl-7-oxa-3- acid azabicyclo[4.2.0]octan-3- yl)methanone(6-phenyl-7-oxa-3- quinoline-8- 6-phenyl-7-oxa-3-azabicyclo[4.2.0]octan-3-yl)- carboxylic acid azabicyclo[4.2.0]octane(8-quinolyl)methanone [(3aS,7aS)-7a-phenyl- 3-methoxy-4-[2-(3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aS)-7a-phenyl-4-(2-fluoro-2- (3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methoxy-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acidc]pyridine propoxy)-3-methoxy- phenyl]methanone [(3aS,7aS)-7a-phenyl-4-(2-hydroxy-2- (3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-hydroxy-2-methyl- acidc]pyridine propoxy)-3-methyl- phenyl]methanone [(3aS,7aS)-7a-phenyl-4-isopropoxy-3- (3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro- methyl-benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-(4-isopropoxy-3-methyl- c]pyridinephenyl)methanone [(3aS,7aS)-7a-phenyl- 4-(2-hydroxy-2-(3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro- methyl-propoxy)-3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic[1,3]dioxolo[4,5- yl]-[4-(2-hydroxy-2-methyl- acid c]pyridinepropoxy)-3-methoxy- phenyl]methanone [(3aS,7aS)-7a-phenyl-4-(1-hydroxy-1- (3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-ethyl)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(1-hydroxy-1-methyl- acidc]pyridine ethyl)-3-methyl- phenyl]methanone [(3aS,7aS)-7a-phenyl-quinoline-8- (3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro- carboxylic acid4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- [1,3]dioxolo[4,5-yl]-(8-quinolyl)methanone c]pyridine [(3aR,7aR)-7a-phenyl-3-methoxy-4-[2- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-phenyl-4-(2-fluoro-2- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methoxy-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acidc]pyridine propoxy)-3-methoxy- phenyl]methanone [(3aR,7aR)-7a-phenyl-4-(2-hydroxy-2- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-hydroxy-2-methyl- acidc]pyridine propoxy)-3-methyl- phenyl]methanone [(3aR,7aR)-7a-phenyl-4-isopropoxy-3- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro- methyl-benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-(4-isopropoxy-3-methyl- c]pyridinephenyl)methanone [(3aR,7aR)-7a-phenyl- 4-(2-hydroxy-2-(3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro- methyl-propoxy)-3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic[1,3]dioxolo[4,5- yl]-[4-(2-hydroxy-2-methyl- acid c]pyridinepropoxy)-3-methoxy- phenyl]methanone [(3aR,7aR)-7a-phenyl-4-(1-hydroxy-1- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-ethyl)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(1-hydroxy-1-methyl- acidc]pyridine ethyl)-3-methyl- phenyl]methanone [(3aR,7aR)-7a-phenyl-quinoline-8- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro- carboxylic acid4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- [1,3]dioxolo[4,5-yl]-(8-quinolyl)methanone c]pyridine [5-cyclopropyl-7- 5-cyclopropyl-7-6-phenyl-3- (trifluoromethyl)-4,5,6,7- (trifluoromethyl)-azabicyclo[4.1.0]heptane tetrahydropyrazolo[1,5- 4,5,6,7-a]pyrimidin-2-yl]-(6-phenyl- tetrahydropyrazolo[1,3-azabicyclo[4.1.0]heptan-3- 5-a]pyrimidine-2- yl)methanone carboxylicacid [6-(4-fluorophenyl)-3- 4-(2-hydroxy-2- 6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptan-3-yl]- methyl-propoxy)-3-azabicyclo[4.1.0]heptane [4-(2-hydroxy-2-methyl- methyl-benzoicpropoxy)-3-methyl- acid phenyl]methanone [4-(2-hydroxy-2-methyl-4-(2-hydroxy-2- (1R,6S)-6-phenyl-3- propoxy)-3-methyl-phenyl]-methyl-propoxy)-3- azabicyclo[4.1.0]heptane [(1R,6S)-6-phenyl-3-methyl-benzoic azabicyclo[4.1.0]heptan-3- acid yl]methanone[4-(2-hydroxy-2-methyl- 4-(2-hydroxy-2- (1S,6R)-6-phenyl-3-propoxy)-3-methyl-phenyl]- methyl-propoxy)-3- azabicyclo[4.1.0]heptane[(1S,6R)-6-phenyl-3- methyl-benzoic azabicyclo[4.1.0]heptan-3- acidyl]methanone [(3aS,7aS)-7a-phenyl- 2- (3aS,7aS)-7a-phenyl-3a,4,6,7-tetrahydro- (trifluoromethoxymethyl)- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 2,3-dihydro- [1,3]dioxolo[4,5- yl]-[2-1,4-benzodioxine- c]pyridine (trifluoromethoxymethyl)-2,3- 6-carboxylicacid dihydro-1,4-benzodioxin-6- yl]methanone [(3aS,7aS)-7a-phenyl-4-(2-fluoro-2- (3aS,7aS)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acidc]pyridine propoxy)-3-methyl- phenyl]methanone [(3aR,7aR)-7a-phenyl- 2-(3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro- (trifluoromethoxymethyl)-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2,3-dihydro-[1,3]dioxolo[4,5- yl]-[2- 1,4-benzodioxine- c]pyridine(trifluoromethoxymethyl)-2,3- 6-carboxylic aciddihydro-1,4-benzodioxin-6- yl]methanone [(3aR,7aR)-7a-phenyl-4-(2-fluoro-2- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acidc]pyridine propoxy)-3-methyl- phenyl]methanone [(3aS,7aS)-7a-(4-3-methoxy-4-[2- (3aS,7aS)-7a-(4- fluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(4-3-methoxy-4-[2- (3aR,7aR)-7a-(4- fluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-pyrimidin-2-3-methoxy-4-[2- (3aR,7aR)-7a-pyrimidin- yl-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 2-yl-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5- acid 3aH-[1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aS)-7a-(1-3-methoxy-4-[2- (3aS,7aS)-7a-(1- methylpyrazol-3-yl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic methylpyrazol-3-yl)-tetrahydro-[1,3]dioxolo[4,5- acid 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aR)-7a-thiazol-2-yl-4-(2-hydroxy-2- (3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-hydroxy-2-methyl- acidc]pyridine propoxy)-3-methyl- phenyl]methanone[(3aS,7aR)-7a-thiazol-2-yl- 4-(2-fluoro-2- (3aS,7aR)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic [1,3]dioxolo[4,5-yl]-[4-(2-fluoro-2-methyl- acid c]pyridine propoxy)-3-methyl-phenyl]methanone [(3aS,7aR)-7a-thiazol-2-yl- 4-(2-fluoro-2-(3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro- methyl-propoxy)-3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic[1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acid c]pyridinepropoxy)-3-methoxy- phenyl]methanone [(3aS,7aR)-7a-thiazol-2-yl-3-methoxy-4-[2- (3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aS)-7a-thiazol-2-yl-4-(2-hydroxy-2- (3aR,7aS)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methyl-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-hydroxy-2-methyl- acidc]pyridine propoxy)-3-methyl- phenyl]methanone[(3aR,7aS)-7a-thiazol-2-yl- 4-(2-fluoro-2- (3aR,7aS)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic [1,3]dioxolo[4,5-yl]-[4-(2-fluoro-2-methyl- acid c]pyridine propoxy)-3-methyl-phenyl]methanone [(3aR,7aS)-7a-thiazol-2-yl- 4-(2-fluoro-2-(3aR,7aS)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro- methyl-propoxy)-3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic[1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acid c]pyridinepropoxy)-3-methoxy- phenyl]methanone [(3aR,7aS)-7a-thiazol-2-yl-3-methoxy-4-[2- (3aR,7aS)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aS)-7a-(4-4-(2-hydroxy-2- (3aS,7aS)-7a-(4- fluorophenyl)-3a,4,6,7-methyl-propoxy)-3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methyl-benzoic tetrahydro-3aH- c]pyridin-5-yl]-[4-(2-hydroxy- acid[1,3]dioxolo[4,5- 2-methyl-propoxy)-3-methyl- c]pyridinephenyl]methanone [(3aS,7aS)-7a-(4- 4-(2-fluoro-2- (3aS,7aS)-7a-(4-fluorophenyl)-3a,4,6,7- methyl-propoxy)-3- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- methyl-benzoic tetrahydro-3aH-c]pyridin-5-yl]-[4-(2-fluoro-2- acid [1,3]dioxolo[4,5-methyl-propoxy)-3-methyl- c]pyridine phenyl]methanone [(3aS,7aS)-7a-(4-4-(2-fluoro-2- (3aS,7aS)-7a-(4- fluorophenyl)-3a,4,6,7-methyl-propoxy)-3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methoxy-benzoic tetrahydro-3aH- c]pyridin-5-yl]-[4-(2-fluoro-2- acid[1,3]dioxolo[4,5- methyl-propoxy)-3-methoxy- c]pyridine phenyl]methanone[(3aS,7aS)-7a-(4- 3-methoxy-4- (3aS,7aS)-7a-(4- fluorophenyl)-3a,4,6,7-(3,3,3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-trifluoropropoxymethyl)benzoic tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- acid [1,3]dioxolo[4,5- (3,3,3- c]pyridinetrifluoropropoxymethyl)phenyl]methanone [(3aR,7aR)-7a-(4-4-(2-hydroxy-2- (3aR,7aR)-7a-(4- fluorophenyl)-3a,4,6,7-methyl-propoxy)-3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methyl-benzoic tetrahydro-3aH- c]pyridin-5-yl]-[4-(2-hydroxy- acid[1,3]dioxolo[4,5- 2-methyl-propoxy)-3-methyl- c]pyridinephenyl]methanone [(3aR,7aR)-7a-(4- 4-(2-fluoro-2- (3aR,7aR)-7a-(4-fluorophenyl)-3a,4,6,7- methyl-propoxy)-3- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- methyl-benzoic tetrahydro-3aH-c]pyridin-5-yl]-[4-(2-fluoro-2- acid [1,3]dioxolo[4,5-methyl-propoxy)-3-methyl- c]pyridine phenyl]methanone [(3aR,7aR)-7a-(4-4-(2-fluoro-2- (3aR,7aR)-7a-(4- fluorophenyl)-3a,4,6,7-methyl-propoxy)-3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methoxy-benzoic tetrahydro-3aH- c]pyridin-5-yl]-[4-(2-fluoro-2- acid[1,3]dioxolo[4,5- methyl-propoxy)-3-methoxy- c]pyridine phenyl]methanone[(3aR,7aR)-7a-(4- 3-methoxy-4- (3aR,7aR)-7a-(4- fluorophenyl)-3a,4,6,7-(3,3,3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-trifluoropropoxymethyl)benzoic tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- acid [1,3]dioxolo[4,5- (3,3,3- c]pyridinetrifluoropropoxymethyl)phenyl]methanone [(3aR,7aR)-7a-pyrimidin-2-4-(2-fluoro-2- (3aR,7aR)-7a-pyrimidin- yl-3a,4,6,7-tetrahydro-methyl-propoxy)-3- 2-yl-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic 3aH-[1,3]dioxolo[4,5-yl]-[4-(2-fluoro-2-methyl- acid c]pyridine propoxy)-3-methyl-phenyl]methanone [(3aR,7aR)-7a-pyrimidin-2- 4-(2-fluoro-2-(3aR,7aR)-7a-pyrimidin- yl-3a,4,6,7-tetrahydro- methyl-propoxy)-3-2-yl-4,5,6,7-tetrahydro- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic3aH-[1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acid c]pyridinepropoxy)-3-methoxy- phenyl]methanone [(3aR,7aR)-7a-pyrimidin-2-4-isopropoxy-3- (3aR,7aR)-7a-pyrimidin- yl-3a,4,6,7-tetrahydro-methyl-benzoic 2-yl-4,5,6,7-tetrahydro- [1,3]dioxolo[4,5-c]pyridin-5-acid 3aH-[1,3]dioxolo[4,5- yl]-(4-isopropoxy-3-methyl- c]pyridinephenyl)methanone [(3aS,7aR)-7a-thiazol-2-yl- 3-methyl-4-[2-(3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5- yl]-[3-methyl-4-[2-c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aS,7aR)-7a-thiazol-2-yl- 6-methoxy-5-[2- (3aS,7aR)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]pyridine-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2-[1,3]dioxolo[4,5- yl]-[6-methoxy-5-[2- carboxylic acid c]pyridine(trifluoromethoxy)ethoxy]-2- pyridyl]methanone[(3aR,7aS)-7a-thiazol-2-yl- 3-methyl-4-[2- (3aR,7aS)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-[3-methyl-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aS)-7a-thiazol-2-yl-6-methoxy-5-[2- (3aR,7aS)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]pyridine- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 2- [1,3]dioxolo[4,5- yl]-[6-methoxy-5-[2-carboxylic acid c]pyridine (trifluoromethoxy)ethoxy]-2-pyridyl]methanone [(3aR,7aR)-7a-thiazol-4-yl- 3-methoxy-4-[2-(3aR,7aR)-7a-thiazol-4- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic yl-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-thiazol-4-yl-3-methyl-4-[2- (3aR,7aR)-7a-thiazol-4- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic yl-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5- yl]-[3-methyl-4-[2-c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-thiazol-4-yl- 4-(2-fluoro-2- (3aR,7aR)-7a-thiazol-4-3a,4,6,7-tetrahydro- methyl-propoxy)-3- yl-4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic [1,3]dioxolo[4,5-yl]-[4-(2-fluoro-2-methyl- acid c]pyridine propoxy)-3-methyl-phenyl]methanone [7a-(2-pyridyl)-3a,4,6,7- 3-methoxy-4-[2-7a-(2-pyridyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]benzoic tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- acid [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-methoxy-4-[2- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-4-(2-fluoro-2- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-methoxy-benzoic [1,3]dioxolo[4,5- yl]-[4-(2-fluoro-2-methyl- acidc]pyridine propoxy)-3-methoxy- phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 4-(2-fluoro-2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic [1,3]dioxolo[4,5-yl]-[4-(2-fluoro-2-methyl- acid c]pyridine propoxy)-3-methyl-phenyl]methanone [(3aR,7aR)-7a-(6-bromo-2- 3-methoxy-4-[2-(3aR,7aR)-7a-(6-bromo-2- pyridyl)-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH- yl]-[3-methoxy-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(2-pyridyl)- 4-(2-hydroxy-2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic [1,3]dioxolo[4,5-yl]-[4-(2-hydroxy-2-methyl- acid c]pyridine propoxy)-3-methyl-phenyl]methanone [(3aR,7aR)-7a-(3-chloro-2- 3-methoxy-4-[2-(3aR,7aR)-7a-(3-chloro-2- pyridyl)-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH- yl]-[3-methoxy-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-chloro-2- 3-methyl-4-[2- (3aR,7aR)-7a-(3-chloro-2-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicpyridyl)-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methyl-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-chloro-2- 4-(2-fluoro-2- (3aR,7aR)-7a-(3-chloro-2-pyridyl)-3a,4,6,7-tetrahydro- methyl-propoxy)-3- pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic tetrahydro-3aH-yl]-[4-(2-fluoro-2-methyl- acid [1,3]dioxolo[4,5- propoxy)-3-methyl-c]pyridine phenyl]methanone [(3aR,7aR)-7a-(3-chloro-2- 5-isopropoxy-6-(3aR,7aR)-7a-(3-chloro-2- pyridyl)-3a,4,6,7-tetrahydro-methyl-pyridine-2- pyridyl)-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5-carboxylic acid tetrahydro-3aH- yl]-(5-isopropoxy-6-methyl-2-[1,3]dioxolo[4,5- pyridyl)methanone c]pyridine[(3aS,7aR)-7a-thiazol-2-yl- 3-methyl-4-(2,2,2-(3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro- trifluoroethoxy)benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-[3-methyl-4-(2,2,2- c]pyridinetrifluoroethoxy)phenyl]methanone [(3aS,7aR)-7a-thiazol-2-yl-3-chloro-4-(2- (3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-hydroxy-2-methyl- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-propoxy)benzoic [1,3]dioxolo[4,5- yl]-[3-chloro-4-(2-hydroxy-2- acidc]pyridine methyl- propoxy)phenyl]methanone [(3aR,7aS)-7a-thiazol-2-yl-3-methyl-4-(2,2,2- (3aR,7aS)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-trifluoroethoxy)benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-methyl-4-(2,2,2- c]pyridine trifluoroethoxy)phenyl]methanone[(3aR,7aS)-7a-thiazol-2-yl- 3-chloro-4-(2- (3aR,7aS)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- hydroxy-2-methyl- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- propoxy)benzoic [1,3]dioxolo[4,5-yl]-[3-chloro-4-(2-hydroxy-2- acid c]pyridine methyl-propoxy)phenyl]methanone [(3aR,7aR)-7a-(3-methoxy-2- 3-methoxy-4-[2-(3aR,7aR)-7a-(3- pyridyl)-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic methoxy-2-pyridyl)-[1,3]dioxolo[4,5-c]pyridin-5- acid 4,5,6,7-tetrahydro-3aH-yl]-[3-methoxy-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-methoxy-2- 3-methyl-4-[2- (3aR,7aR)-7a-(3-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicmethoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- acid4,5,6,7-tetrahydro-3aH- yl]-[3-methyl-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-methoxy-2- 3-chloro-4-[2- (3aR,7aR)-7a-(3-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicmethoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- acid4,5,6,7-tetrahydro-3aH- yl]-[3-chloro-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-methoxy-2- 4-(2-fluoro-2- (3aR,7aR)-7a-(3-pyridyl)-3a,4,6,7-tetrahydro- methyl-propoxy)-3- methoxy-2-pyridyl)-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic 4,5,6,7-tetrahydro-3aH-yl]-[4-(2-fluoro-2-methyl- acid [1,3]dioxolo[4,5- propoxy)-3-methyl-c]pyridine phenyl]methanone [(3aR,7aR)-7a-(3-fluoro-2- 3-methoxy-4-[2-(3aR,7aR)-7a-(3-fluoro-2- pyridyl)-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH- yl]-[3-methoxy-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-fluoro-2- 3-methyl-4-[2- (3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicpyridyl)-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methyl-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-fluoro-2- 4-(2-fluoro-2- (3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro- methyl-propoxy)-3- pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- methyl-benzoic tetrahydro-3aH-yl]-[4-(2-fluoro-2-methyl- acid [1,3]dioxolo[4,5- propoxy)-3-methyl-c]pyridine phenyl]methanone [(3aR,7aR)-7a-(3-fluoro-2- 3-chloro-4-[2-(3aR,7aR)-7a-(3-fluoro-2- pyridyl)-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH- yl]-[3-chloro-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(3-fluoro-2- 6-methoxy-5-[2- (3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]pyridine-2-pyridyl)-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- carboxylic acidtetrahydro-3aH- yl]-[6-methoxy-5-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]-2- c]pyridine pyridyl]methanone[(3aR,7aR)-7a-(2- 3-methoxy-4-[2- (3aR,7aR)-7a-(2-methylthiazol-4-yl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicmethylthiazol-4-yl)- tetrahydro-[1,3]dioxolo[4,5- acid4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5-[2- c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-(2- 3-methyl-4-[2- (3aR,7aR)-7a-(2-methylthiazol-4-yl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicmethylthiazol-4-yl)- tetrahydro-[1,3]dioxolo[4,5- acid4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methyl-4- [1,3]dioxolo[4,5-[2- c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-(2- 4-(2-fluoro-2- (3aR,7aR)-7a-(2-methylthiazol-4-yl)-3a,4,6,7- methyl-propoxy)-3- methylthiazol-4-yl)-tetrahydro-[1,3]dioxolo[4,5- methyl-benzoic 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[4-(2-fluoro-2- acid [1,3]dioxolo[4,5-methyl-propoxy)-3-methyl- c]pyridine phenyl]methanone [(3aR,7aR)-7a-(2-3-chloro-4-[2- (3aR,7aR)-7a-(2- methylthiazol-4-yl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic methylthiazol-4-yl)-tetrahydro-[1,3]dioxolo[4,5- acid 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[3-chloro-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2-6-methoxy-5-[2- (3aR,7aR)-7a-(2- methylthiazol-4-yl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- methylthiazol-4-yl)-tetrahydro-[1,3]dioxolo[4,5- 2- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aS,7aR)-7a-thiazol-2-yl- 3-chloro-4-[2- (3aS,7aR)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-[3-chloro-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aS)-7a-thiazol-2-yl-3-chloro-4-[2- (3aR,7aS)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5- yl]-[3-chloro-4-[2-c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 6-methoxy-5-[2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]pyridine-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2-[1,3]dioxolo[4,5- yl]-[6-methoxy-5-[2- carboxylic acid c]pyridine(trifluoromethoxy)ethoxy]-2- pyridyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 3-methyl-4-[2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-[3-methyl-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-chloro-4-[2- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5- yl]-[3-chloro-4-[2-c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[4-(2-hydroxy-1,1-dimethyl- 4-(2-hydroxy-1,1- 6-phenyl-3-ethyl)-3-methoxy-phenyl]-(6- dimethyl-ethyl)-3- azabicyclo[4.1.0]heptanephenyl-3- methoxy-benzoic azabicyclo[4.1.0]heptan-3- acid yl)methanone[(3aS,7aR)-7a-thiazol-2-yl- 6-ethoxy-5-[2- (3aS,7aR)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]pyridine-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2-[1,3]dioxolo[4,5- yl]-[6-ethoxy-5-[2- carboxylic acid c]pyridine(trifluoromethoxy)ethoxy]-2- pyridyl]methanone[(3aR,7aS)-7a-thiazol-2-yl- 6-ethoxy-5-[2- (3aR,7aS)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]pyridine-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2-[1,3]dioxolo[4,5- yl]-[6-ethoxy-5-[2- carboxylic acid c]pyridine(trifluoromethoxy)ethoxy]-2- pyridyl]methanone [(3aR,7aR)-7a-(2-6-ethoxy-5-[2- (3aR,7aR)-7a-(2- methylthiazol-4-yl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- methylthiazol-4-yl)-tetrahydro-[1,3]dioxolo[4,5- 2- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[6-ethoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aS)-7a-thiazol-2-yl- 3-fluoro-4-[2- (3aR,7aS)-7a-thiazol-2-yl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-[3-fluoro-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aR)-7a-thiazol-2-yl-3-fluoro-4-[2- (3aS,7aR)-7a-thiazol-2-yl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5- yl]-[3-fluoro-4-[2-c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 3-chloro-4-(2,2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- dimethylpropoxy)benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-chloro-4-(2,2- c]pyridine dimethylpropoxy)phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 3-chloro-4-[2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- (2,2,2- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- trifluoroethoxy)ethoxy]benzoic[1,3]dioxolo[4,5- yl]-[3-chloro-4-[2-(2,2,2- acid c]pyridinetrifluoroethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-chloro-4-(4,4,4- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-trifluoro-2-methyl- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- butoxy)benzoic [1,3]dioxolo[4,5-yl]-[3-chloro-4-(4,4,4- acid c]pyridine trifluoro-2-methyl-butoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 3-chloro-4-[(3,3-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-difluorocyclobutyl)methoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-chloro-4-[(3,3- c]pyridinedifluorocyclobutyl)methoxy]phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-chloro-4-(2,2,3,3- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-tetrafluoropropoxy)benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-chloro-4-(2,2,3,3- c]pyridine tetrafluoropropoxy)phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 6-methyl-5-[2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]pyridine-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2-[1,3]dioxolo[4,5- yl]-[6-methyl-5-[2- carboxylic acid c]pyridine(trifluoromethoxy)ethoxy]-2- pyridyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 3-(trifluoromethyl)-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- 4-(3,3,3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-trifluoropropoxy)benzoic [1,3]dioxolo[4,5- yl]-[3-(trifluoromethyl)-4-acid c]pyridine (3,3,3- trifluoropropoxy)phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 4-(2-fluoro-2- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- methyl-propoxy)-3- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- (trifluoromethyl)benzoic [1,3]dioxolo[4,5-yl]-[4-(2-fluoro-2-methyl- acid c]pyridine propoxy)-3-(trifluoromethyl)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-chloro-4-(2- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-fluoro-2-methyl- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-propoxy)benzoic [1,3]dioxolo[4,5- yl]-[3-chloro-4-(2-fluoro-2- acidc]pyridine methyl- propoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-chloro-4- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-hydroxy-benzoic 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-acid [1,3]dioxolo[4,5- yl]-(3-chloro-4-hydroxy- c]pyridinephenyl)methanone [(3aR,7aR)-7a-(2-pyridyl)- 3-chloro-4-(2,2-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- difluoropropoxy)benzoic4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- acid[1,3]dioxolo[4,5- yl]-[3-chloro-4-(2,2- c]pyridinedifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-chloro-4-(2,2,2- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-trifluoro-1-methyl- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- ethoxy)benzoic acid [1,3]dioxolo[4,5-yl]-[3-chloro-4-(2,2,2- c]pyridine trifluoro-1-methyl-ethoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 3-chloro-4-[(2,2-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-difluorocyclopropyl)methoxy]benzoic 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- acid [1,3]dioxolo[4,5-yl]-[3-chloro-4-[(2,2- c]pyridinedifluorocyclopropyl)methoxy]phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-4-(2-tert- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-butoxyethoxy)-3- 4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-chloro-benzoic acid [1,3]dioxolo[4,5- yl]-[4-(2-tert-butoxyethoxy)-c]pyridine 3-chloro-phenyl]methanone [7a-(2-pyridyl)-2,3,3a,4,6,7-3-methoxy-4-[2- 7a-(2-pyridyl)- hexahydrofuro[3,2-c]pyridin-(trifluoromethoxy)ethoxy]benzoic 3,3a,4,5,6,7-hexahydro-5-yl]-[3-methoxy-4-[2- acid 2H-furo[3,2-c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(6-methyl-2-3-methoxy-4-[2- (3aR,7aR)-7a-(6-methyl- pyridyl)-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]benzoic 2-pyridyl)-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH- yl]-[3-methoxy-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(6-methyl-2- 3-methyl-4-[2- (3aR,7aR)-7a-(6-methyl-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoic2-pyridyl)-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methyl-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(6-methoxy-2- 3-methoxy-4-[2- (3aR,7aR)-7a-(6-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicmethoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- acid4,5,6,7-tetrahydro-3aH- yl]-[3-methoxy-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(6-methoxy-2- 3-methyl-4-[2- (3aR,7aR)-7a-(6-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicmethoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- acid4,5,6,7-tetrahydro-3aH- yl]-[3-methyl-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(6-isobutoxy- 3-methoxy-4-[2- (3aR,7aR)-7a-(6-2-pyridyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicisobutoxy-2-pyridyl)- tetrahydro-[1,3]dioxolo[4,5- acid4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5-[2- c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-(6-isobutoxy- 3-methyl-4-[2- (3aR,7aR)-7a-(6-2-pyridyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicisobutoxy-2-pyridyl)- tetrahydro-[1,3]dioxolo[4,5- acid4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methyl-4- [1,3]dioxolo[4,5-[2- c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- [(3aS,7aS)-7a-(2- (3aR,7aR)-7a-(2-pyridyl)-1,3,3a,4,6,7- pyridyl)- 3,3a,4,5,6,7-hexahydro-hexahydrofuro[3,4-c]pyridin- 1,3,3a,4,6,7- 1H-furo[3,4-c]pyridine5-yl]-[3-methoxy-4-[2- hexahydrofuro[3,4-(trifluoromethoxy)ethoxy]phenyl]methanone; c]pyridin-5-yl]-[3-[(3aS,7aS)-7a- methoxy-4-[2- (2-pyridyl)-1,3,3a,4,6,7-(trifluoromethoxy)ethoxy]phenyl]methanone; hexahydrofuro[3,4-c]pyridin-3-methoxy- 5-yl]-[3-methoxy-4-[2- 4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone(trifluoromethoxy)ethoxy]benzoic acid [(3aR,7aR)-7a-phenyl- 3-methoxy-4-(3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro- (2,2,2-trifluoro-1-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methyl-[1,3]dioxolo[4,5- yl]-[3-methoxy-4-(2,2,2- ethoxy)benzoic acidc]pyridine trifluoro-1-methyl- ethoxy)phenyl]methanone[(3aR,7aR)-7a-phenyl- 4-[(3,3- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-difluorocyclobutyl)methoxy]- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 3- [1,3]dioxolo[4,5- yl]-[4-[(3,3-methoxy-benzoic c]pyridine difluorocyclobutyl)methoxy]- acid3-methoxy-phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 3-methoxy-4-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- (2,2,2-trifluoro-1-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methyl-[1,3]dioxolo[4,5- yl]-[3-methoxy-4-(2,2,2- ethoxy)benzoic acidc]pyridine trifluoro-1-methyl- ethoxy)phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 4-[(3,3- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- difluorocyclobutyl)methoxy]-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 3-[1,3]dioxolo[4,5- yl]-[4-[(3,3- methoxy-benzoic c]pyridinedifluorocyclobutyl)methoxy]- acid 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 3-fluoro-5- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- methoxy-4-(3,3,3- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- trifluoropropoxy)benzoic [1,3]dioxolo[4,5-yl]-[3-fluoro-5-methoxy-4- acid c]pyridine (3,3,3-trifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 4-[(2,2-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-difluorocyclopropyl)methoxy]- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 3- [1,3]dioxolo[4,5- yl]-[4-[(2,2-(trifluoromethyl)benzoic c]pyridine difluorocyclopropyl)methoxy]- acid3- (trifluoromethyl)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-4-(2,2,3,3- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-tetrafluoropropoxy)- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 3- [1,3]dioxolo[4,5- yl]-[4-(2,2,3,3-(trifluoromethyl)benzoic c]pyridine tetrafluoropropoxy)-3- acid(trifluoromethyl)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 3-chloro-5-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- methoxy-4-[2-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-(trifluoromethoxy)ethoxy]benzoic [1,3]dioxolo[4,5-yl]-[3-chloro-5-methoxy-4-[2- acid c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(4aR,8aR)-8a-phenyl-3-methoxy-4-[2- (4aR,8aR)-8a-phenyl- 2,3,4a,5,7,8-hexahydro-(trifluoromethoxy)ethoxy]benzoic 3,4a,5,6,7,8-hexahydro-[1,4]dioxino[2,3-c]pyridin-6- acid 2H-[1,4]dioxino[2,3-yl]-[3-methoxy-4-[2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-phenyl-3-methoxy-4- (3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro- (3,3,3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-trifluoropropoxy)benzoic [1,3]dioxolo[4,5- yl]-[3-methoxy-4-(3,3,3- acidc]pyridine trifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-methoxy-4- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- (3,3,3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-trifluoropropoxy)benzoic [1,3]dioxolo[4,5- yl]-[3-methoxy-4-(3,3,3- acidc]pyridine trifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)-3-methoxy-4- (3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-(3,3,3-trifluoro-1- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- methyl- [1,3]dioxolo[4,5-yl]-[3-methoxy-4-(3,3,3- propoxy)benzoic c]pyridine trifluoro-1-methyl-acid propoxy)phenyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 4-(2,2-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- difluoropropoxy)-3-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5-(trifluoromethyl)benzoic [1,3]dioxolo[4,5- yl]-[4-(2,2-difluoropropoxy)-acid c]pyridine 3- (trifluoromethyl)phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 4-[(3,3- (3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro- difluorocyclobutyl)methoxy]-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 3-[1,3]dioxolo[4,5- yl]-[4-[(3,3- (trifluoromethyl)benzoic c]pyridinedifluorocyclobutyl)methoxy]- acid 3- (trifluoromethyl)phenyl]methanone[(3aR,7aR)-7a-(2-pyridyl)- 3-(trifluoromethyl)-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro- 4-(2,2,2-trifluoro-1-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- methyl-[1,3]dioxolo[4,5- yl]-[3-(trifluoromethyl)-4- ethoxy)benzoic acidc]pyridine (2,2,2-trifluoro-1-methyl- ethoxy)phenyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 3-methoxy-4-[2- (3aR,7aR)-2,2-dideuterio-(3,5-difluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoic7a-(3,5-difluorophenyl)- tetrahydro-[1,3]dioxolo[4,5- acid4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5-[2- c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 3-methoxy-4- (3aR,7aR)-2,2-dideuterio-(3,5-difluorophenyl)-3a,4,6,7- (2,2,2-trifluoro-1-7a-(3,5-difluorophenyl)- tetrahydro-[1,3]dioxolo[4,5- methyl-4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy)benzoicacid [1,3]dioxolo[4,5- (2,2,2-trifluoro-1-methyl- c]pyridineethoxy)phenyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 4-[(3,3-(3aR,7aR)-2,2-dideuterio- (3,5-difluorophenyl)-3a,4,6,7-difluorocyclobutyl)methoxy]- 7a-(3,5-difluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 3- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 6-methoxy-5-[2- (3aR,7aR)-2,2-dideuterio-(3,5-difluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]pyridine-7a-(3,5-difluorophenyl)- tetrahydro-[1,3]dioxolo[4,5- 2-4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid[1,3]dioxolo[4,5- [2-(trifluoromethoxy)ethoxy]- c]pyridine2-pyridyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 6-methyl-5-[2-(3aR,7aR)-2,2-dideuterio- (3,5-difluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- 7a-(3,5-difluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 2- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[6-methyl-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 3-methoxy-4-[2- (3aR,7aR)-2,2-dideuterio-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoic7a-(3-fluorophenyl)- tetrahydro-[1,3]dioxolo[4,5- acid4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5-[2- c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 3-methoxy-4- (3aR,7aR)-2,2-dideuterio-(3-fluorophenyl)-3a,4,6,7- (2,2,2-trifluoro-1- 7a-(3-fluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- methyl- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- ethoxy)benzoic acid [1,3]dioxolo[4,5-(2,2,2-trifluoro-1-methyl- c]pyridine ethoxy)phenyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 4-[(3,3- (3aR,7aR)-2,2-dideuterio-(3-fluorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-7a-(3-fluorophenyl)- tetrahydro-[1,3]dioxolo[4,5- 3-4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic[1,3]dioxolo[4,5- difluorocyclobutyl)methoxy]- acid c]pyridine3-methoxy-phenyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 6-methoxy-5-[2-(3aR,7aR)-2,2-dideuterio- (3-fluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- 7a-(3-fluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 2- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 6-methyl-5-[2- (3aR,7aR)-2,2-dideuterio-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]pyridine-7a-(3-fluorophenyl)- tetrahydro-[1,3]dioxolo[4,5- 2-4,5,6,7-tetrahydro-3aH- c]pyridin-5-yl]-[6-methyl-5- carboxylic acid[1,3]dioxolo[4,5- [2-(trifluoromethoxy)ethoxy]- c]pyridine2-pyridyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 3-methoxy-4-[2-(3aR,7aR)-2,2-dideuterio- (2-pyridyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic 7a-(2-pyridyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-2,2-dideuterio-7a-3-chloro-4-[2- (3aR,7aR)-2,2-dideuterio- (2-pyridyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic 7a-(2-pyridyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-chloro-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-2,2-dideuterio-7a-6-methyl-5-[2- (3aR,7aR)-2,2-dideuterio- (2-pyridyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- 7a-(2-pyridyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methyl-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 3-methoxy-4-[2- (3aR,7aR)-2,2-dideuterio-phenyl-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoic7a-phenyl-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methoxy-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine [3-chloro-4-[2-3-chloro-4-[2- 6-(4-fluorophenyl)-3- (trifluoromethoxy)ethoxy]phenyl]-(trifluoromethoxy)ethoxy]benzoic azabicyclo[4.1.0]heptane[6-(4-fluorophenyl)-3- acid azabicyclo[4.1.0]heptan-3- yl]methanone[6-(4-fluorophenyl)-3- 3-methoxy-4-[2- 6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptan-3-yl]- (trifluoromethoxy)ethoxy]benzoicazabicyclo[4.1.0]heptane [3-methoxy-4-[2- acid(trifluoromethoxy)ethoxy]phenyl]methanone [6-(4-fluorophenyl)-3-6-methoxy-5-[2- 6-(4-fluorophenyl)-3- azabicyclo[4.1.0]heptan-3-yl]-(trifluoromethoxy)ethoxy]pyridine- azabicyclo[4.1.0]heptane[6-methoxy-5-[2- 2- (trifluoromethoxy)ethoxy]-2- carboxylic acidpyridyl]methanone [4-[(3,3- 4-[(3,3- 6-(4-fluorophenyl)-3-difluorocyclobutyl)methoxy]- difluorocyclobutyl)methoxy]-azabicyclo[4.1.0]heptane 3-methoxy-phenyl]-[6-(4- 3- fluorophenyl)-3-methoxy-benzoic azabicyclo[4.1.0]heptan-3- acid yl]methanone[6-(4-fluorophenyl)-3- 3-methoxy-4- 6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptan-3-yl]- (2,2,2-trifluoro-1-azabicyclo[4.1.0]heptane [3-methoxy-4-(2,2,2-trifluoro- methyl-1-methyl- ethoxy)benzoic acid ethoxy)phenyl]methanone [5-chloro-6-[2-5-chloro-6-[2- 6-(4-fluorophenyl)-3- (trifluoromethoxy)ethoxy]-3-(trifluoromethoxy)ethoxy]pyridine- azabicyclo[4.1.0]heptanepyridyl]-[6-(4-fluorophenyl)- 3- 3-azabicyclo[4.1.0]heptan-3- carboxylicacid yl]methanone [(3aR,7aR)-7a-phenyl- 5-chloro-6-[2-(3aR,7aR)-7a-phenyl- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]pyridine- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 3- [1,3]dioxolo[4,5- yl]-[5-chloro-6-[2-carboxylic acid c]pyridine (trifluoromethoxy)ethoxy]-3-pyridyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 5-chloro-6-[2-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]pyridine- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 3- [1,3]dioxolo[4,5- yl]-[5-chloro-6-[2-carboxylic acid c]pyridine (trifluoromethoxy)ethoxy]-3-pyridyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 6-methoxy-5-[2-(3aR,7aR)-2,2-dideuterio- phenyl-3a,4,6,7-tetrahydro-(trifluoromethoxy)ethoxy]pyridine- 7a-phenyl-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- 2- tetrahydro-3aH- yl]-[6-methoxy-5-[2-carboxylic acid [1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]-2-c]pyridine pyridyl]methanone 3-[(3aR,7aR)-5-[3-methoxy- 3-methoxy-4-[2-3-[(3aR,7aR)-4,5,6,7- 4-[2- (trifluoromethoxy)ethoxy]benzoictetrahydro-3aH- (trifluoromethoxy)ethoxy]benzoyl]- acid[1,3]dioxolo[4,5- 3a,4,6,7-tetrahydro- c]pyridin-7a-[1,3]dioxolo[4,5-c]pyridin-7a- yl]benzonitrile yl]benzonitrile3-[(3aR,7aR)-5-[6-methoxy- 6-methoxy-5-[2- 3-[(3aR,7aR)-4,5,6,7- 5-[2-(trifluoromethoxy)ethoxy]pyridine- tetrahydro-3aH-(trifluoromethoxy)ethoxy]pyridine- 2- [1,3]dioxolo[4,5-2-carbonyl]-3a,4,6,7- carboxylic acid c]pyridin-7a-tetrahydro-[1,3]dioxolo[4,5- yl]benzonitrilec]pyridin-7a-yl]benzonitrile 3-[(3aR,7aR)-5-[4-[(3,3- 4-[(3,3-3-[(3aR,7aR)-4,5,6,7- difluorocyclobutyl)methoxy]-difluorocyclobutyl)methoxy]- tetrahydro-3aH-3-methoxy-benzoyl]-3a,4,6,7- 3- [1,3]dioxolo[4,5-tetrahydro-[1,3]dioxolo[4,5- methoxy-benzoic c]pyridin-7a-c]pyridin-7a-yl]benzonitrile acid yl]benzonitrile3-[(3aR,7aR)-5-[3-methoxy- 3-methoxy-4- 3-[(3aR,7aR)-4,5,6,7-4-(2,2,2-trifluoro-1-methyl- (2,2,2-trifluoro-1- tetrahydro-3aH-ethoxy)benzoyl]-3a,4,6,7- methyl- [1,3]dioxolo[4,5-tetrahydro-[1,3]dioxolo[4,5- ethoxy)benzoic acid c]pyridin-7a-c]pyridin-7a-yl]benzonitrile yl]benzonitrile [(3aR,7aR)-7a-(2,5-3-methoxy-4-[2- (3aR,7aR)-7a-(2,5- difluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic difluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2,5-6-methoxy-5-[2- (3aR,7aR)-7a-(2,5- difluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- difluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-7a-(2,5- 4-[(3,3- (3aR,7aR)-7a-(2,5-difluorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-(2,5- 3-methoxy-4- (3aR,7aR)-7a-(2,5-difluorophenyl)-3a,4,6,7- (3,3,3- difluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- trifluoropropoxy)benzoic tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- acid [1,3]dioxolo[4,5- (3,3,3- c]pyridinetrifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(2,5- 3-methoxy-4-(3aR,7aR)-7a-(2,5- difluorophenyl)-3a,4,6,7- (2,2,2-trifluoro-1-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy)benzoic acid[1,3]dioxolo[4,5- (2,2,2-trifluoro-1-methyl- c]pyridineethoxy)phenyl]methanone [3-methoxy-4-[2- 3-methoxy-4-[2-6-(2-pyridyl)-3- (trifluoromethoxy)ethoxy]phenyl]-(trifluoromethoxy)ethoxy]benzoic azabicyclo[4.1.0]heptane[6-(2-pyridyl)-3- acid azabicyclo[4.1.0]heptan-3- yl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 5- (3aR,7aR)-2,2-dideuterio-(3-fluorophenyl)-3a,4,6,7- (cyclobutylmethoxy)- 7a-(3-fluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 6-methoxy- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[5- pyridine-2- [1,3]dioxolo[4,5- (cyclobutylmethoxy)-6-carboxylic acid c]pyridine methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3-4-[(3,3- (3aR,7aR)-7a-(3- chlorophenyl)-3a,4,6,7-difluorocyclobutyl)methoxy]- chlorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-(3- 3-methoxy-4-[2- (3aR,7aR)-7a-(3-chlorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicchlorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(3- 3-methoxy-4-(3aR,7aR)-7a-(3- chlorophenyl)-3a,4,6,7- (3,3,3- chlorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- trifluoropropoxy)benzoic tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- acid [1,3]dioxolo[4,5- (3,3,3- c]pyridinetrifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(3- 3-methoxy-4-(3aR,7aR)-7a-(3- chlorophenyl)-3a,4,6,7- (2,2,2-trifluoro-1-chlorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy)benzoic acid[1,3]dioxolo[4,5- (2,2,2-trifluoro-1-methyl- c]pyridineethoxy)phenyl]methanone [(3aR,7aR)-7a-(2,3- 4-[(3,3- (3aR,7aR)-7a-(2,3-difluorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-(2,3- 3-methoxy-4-[2- (3aR,7aR)-7a-(2,3-difluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicdifluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- acidtetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2-c]pyridine (trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2,3-3-methoxy-4- (3aR,7aR)-7a-(2,3- difluorophenyl)-3a,4,6,7- (3,3,3-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-trifluoropropoxy)benzoic tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4-acid [1,3]dioxolo[4,5- (3,3,3- c]pyridinetrifluoropropoxy)phenyl]methanone [(3aR,7aR)-7a-(2,3- 3-methoxy-4-(3aR,7aR)-7a-(2,3- difluorophenyl)-3a,4,6,7- (2,2,2-trifluoro-1-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy)benzoic acid[1,3]dioxolo[4,5- (2,2,2-trifluoro-1-methyl- c]pyridineethoxy)phenyl]methanone [(3aR,7aR)-7a-(3- 6-methoxy-5-[2-(3aR,7aR)-7a-(3- chlorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]pyridine- chlorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-7a-(2,3- 6-methoxy-5-[2- (3aR,7aR)-7a-(2,3-difluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]pyridine-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-7a-(2,3- 5-[(3,3- (3aR,7aR)-7a-(2,3-difluorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 6- tetrahydro-3aH-c]pyridin-5-yl]-[5-[(3,3- methoxy-pyridine- [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- 2-carboxylic acid c]pyridine 6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3- 5-[(3,3- (3aR,7aR)-7a-(3-chlorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-chlorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 6- tetrahydro-3aH-c]pyridin-5-yl]-[5-[(3,3- methoxy-pyridine- [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- 2-carboxylic acid c]pyridine 6-methoxy-2-pyridyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 5-[(3,3-(3aR,7aR)-2,2-dideuterio- (3,5-difluorophenyl)-3a,4,6,7-difluorocyclobutyl)methoxy]- 7a-(3,5-difluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 6- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[5-[(3,3- methoxy-pyridine- [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- 2-carboxylic acid c]pyridine 6-methoxy-2-pyridyl]methanone [(3aR,7aR)-2,2-dideuterio-7a- 5-[(3,3-(3aR,7aR)-2,2-dideuterio- (3-fluorophenyl)-3a,4,6,7-difluorocyclobutyl)methoxy]- 7a-(3-fluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 6- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[5-[(3,3- methoxy-pyridine- [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- 2-carboxylic acid c]pyridine 6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 3-methoxy-4-[2-(3aR,7aR)-7a-(2-pyridyl)- 1,3,3a,4,6,7- (trifluoromethoxy)ethoxy]benzoic3,3a,4,5,6,7-hexahydro- hexahydrofuro[3,4-c]pyridin- acid1H-furo[3,4-c]pyridine 5-yl]-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]methanone (3aS,7aS)-5-[3-methoxy-4-[2-3-methoxy-4-[2- (3aS,7aS)-7a-(2-pyridyl)-(trifluoromethoxy)ethoxy]benzoyl]- (trifluoromethoxy)ethoxy]benzoic3,3a,4,5,6,7- 7a-(2-pyridyl)-3a,4,6,7- acid hexahydrofuro[3,4-tetrahydro-3H-furo[3,4- c]pyridin-1-one c]pyridin-1-one[(3aR,7aR)-7a-(3- 4-[(3,3- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-difluorocyclobutyl)methoxy]- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-(3- 6-methoxy-5-[2- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]pyridine-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aS,7aS)-7a-(2-pyridyl)- 3-methoxy-4-[2- (3aS,7aS)-7a-(2-pyridyl)-1,3,3a,4,6,7- (trifluoromethoxy)ethoxy]benzoic 3,3a,4,5,6,7-hexahydro-hexahydrofuro[3,4-c]pyridin- acid 1H-furo[3,4-c]pyridine5-yl]-[3-methoxy-4-[2- (trifluoromethoxy)ethoxy]phenyl]methanone[(3aR,7aR)-7a-[6- 3-methoxy-4-[2- (3aR,7aR)-7a-[6-(trifluoromethyl)-2-pyridyl]- (trifluoromethoxy)ethoxy]benzoic(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- acid pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- tetrahydro-3aH- yl]-[3-methoxy-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-[6- 4-[(3,3- (3aR,7aR)-7a-[6-(trifluoromethyl)-2-pyridyl]- difluorocyclobutyl)methoxy]-(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- 3- pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic tetrahydro-3aH-yl]-[4-[(3,3- acid [1,3]dioxolo[4,5- difluorocyclobutyl)methoxy]-c]pyridine 3-methoxy-phenyl]methanone [(3aR,7aR)-7a-[6- 3-methoxy-4-(3aR,7aR)-7a-[6- (trifluoromethyl)-2-pyridyl]- (3,3,3-(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- trifluoropropoxy)benzoicpyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methoxy-4-(3,3,3- [1,3]dioxolo[4,5-trifluoropropoxy)phenyl]methanone c]pyridine [(3aR,7aR)-7a-[6-3-methoxy-4- (3aR,7aR)-7a-[6- (trifluoromethyl)-2-pyridyl]-(2,2,2-trifluoro-1- (trifluoromethyl)-2- 3a,4,6,7-tetrahydro- methyl-pyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- ethoxy)benzoic acidtetrahydro-3aH- yl]-[3-methoxy-4-(2,2,2- [1,3]dioxolo[4,5-trifluoro-1-methyl- c]pyridine ethoxy)phenyl]methanone [(3aR,7aR)-7a-[6-6-methoxy-5-[2- (3aR,7aR)-7a-[6- (trifluoromethyl)-2-pyridyl]-(trifluoromethoxy)ethoxy]pyridine- (trifluoromethyl)-2-3a,4,6,7-tetrahydro- 2- pyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5-carboxylic acid tetrahydro-3aH- yl]-[6-methoxy-5-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]-2- c]pyridine pyridyl]methanone[(3aR,7aR)-7a-(2,3- 6-methoxy-5-[[1- (3aR,7aR)-7a-(2,3-difluorophenyl)-3a,4,6,7- (trifluoromethyl)cyclopropyl]methoxy]pyridine-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5- [[1-c]pyridine (trifluoromethyl)cyclopropyl]methoxy]- 2- pyridyl]methanone[(3aR,7aR)-7a-(3- 6-methoxy-5-[[1- (3aR,7aR)-7a-(3-chlorophenyl)-3a,4,6,7- (trifluoromethyl)cyclopropyl]methoxy]pyridine-chlorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5- [[1-c]pyridine (trifluoromethyl)cyclopropyl]methoxy]- 2- pyridyl]methanone[(3aR,7aR)-2,2-dideuterio-7a- 6-methoxy-5-[[1- (3aR,7aR)-2,2-dideuterio-(3,5-difluorophenyl)-3a,4,6,7-(trifluoromethyl)cyclopropyl]methoxy]pyridine- 7a-(3,5-difluorophenyl)-tetrahydro-[1,3]dioxolo[4,5- 2- 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5- [[1-c]pyridine (trifluoromethyl)cyclopropyl]methoxy]- 2- pyridyl]methanone[(3aR,7aR)-7a-(3- 6-methoxy-5-[[1- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (trifluoromethyl)cyclopropyl]methoxy]pyridine-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5- [[1-c]pyridine (trifluoromethyl)cyclopropyl]methoxy]- 2- pyridyl]methanone[(3aR,7aR)-7a-[6- 5-[(3,3- (3aR,7aR)-7a-[6-(trifluoromethyl)-2-pyridyl]- difluorocyclobutyl)methoxy]-(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- 6- pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- methoxy-pyridine- tetrahydro-3aH-yl]-[5-[(3,3- 2-carboxylic acid [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- c]pyridine 6-methoxy-2- pyridyl]methanone[3-methoxy-4-[2- 3-methoxy-4-[2- (1S,6R)-6-(2-pyridyl)-3-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoicazabicyclo[4.1.0]heptane [(1S,6R)-6-(2-pyridyl)-3- acidazabicyclo[4.1.0]heptan-3- yl]methanone [3-methoxy-4-[2- 3-methoxy-4-[2-(1R,6S)-6-(2-pyridyl)-3- (trifluoromethoxy)ethoxy]phenyl]-(trifluoromethoxy)ethoxy]benzoic azabicyclo[4.1.0]heptane[(1R,6S)-6-(2-pyridyl)-3- acid azabicyclo[4.1.0]heptan-3- yl]methanone[(3aR,7aR)-7a-phenyl- 6-methoxy-5-[[1- (3aR,7aR)-7a-phenyl-3a,4,6,7-tetrahydro- (trifluoromethyl)cyclopropyl]methoxy]pyridine-4,5,6,7-tetrahydro-3aH- [1,3]dioxolo[4,5-c]pyridin-5- 2-[1,3]dioxolo[4,5- yl]-[6-methoxy-5-[[1- carboxylic acid c]pyridine(trifluoromethyl)cyclopropyl]methoxy]- 2- pyridyl]methanone[(3aR,7aR)-7a-(3- 6-methoxy-5- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-(2,2,2-trifluoro-1- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methyl- tetrahydro-3aH- c]pyridin-5-yl]-[6-methoxy-5- ethoxy)pyridine-2-[1,3]dioxolo[4,5- (2,2,2-trifluoro-1-methyl- carboxylic acid c]pyridineethoxy)-2-pyridyl]methanone [(3aR,7aR)-7a-(3- 6-methoxy-5-(3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7- (2,2,3,3-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-tetrafluoropropoxy)pyridine- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- 2- [1,3]dioxolo[4,5-(2,2,3,3-tetrafluoropropoxy)- carboxylic acid c]pyridine2-pyridyl]methanone [(3aR,7aR)-7a-(2,3- 6-methoxy-5- (3aR,7aR)-7a-(2,3-difluorophenyl)-3a,4,6,7- (2,2,2-trifluoro-1- difluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- methyl- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- ethoxy)pyridine-2- [1,3]dioxolo[4,5-(2,2,2-trifluoro-1-methyl- carboxylic acid c]pyridineethoxy)-2-pyridyl]methanone [(3aR,7aR)-7a-(2,3- 6-methoxy-5-(3aR,7aR)-7a-(2,3- difluorophenyl)-3a,4,6,7- (2,2,3,3-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-tetrafluoropropoxy)pyridine- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- 2- [1,3]dioxolo[4,5-(2,2,3,3-tetrafluoropropoxy)- carboxylic acid c]pyridine2-pyridyl]methanone [(3aR,7aR)-7a-(2-pyridyl)- 6-methoxy-5-[[1-(3aR,7aR)-7a-(2-pyridyl)- 3a,4,6,7-tetrahydro-(trifluoromethyl)cyclopropyl]methoxy]pyridine- 4,5,6,7-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyridin-5- 2- [1,3]dioxolo[4,5- yl]-[6-methoxy-5-[[1-carboxylic acid c]pyridine (trifluoromethyl)cyclopropyl]methoxy]- 2-pyridyl]methanone [(3aR,7aR)-7a-(3- 4- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (difluoromethylsulfonyl)benzoicfluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[4- [1,3]dioxolo[4,5-(difluoromethylsulfonyl)phenyl]methanone c]pyridine[7,7-difluoro-6-(2-pyridyl)-3- 3-methoxy-4-[2-7,7-difluoro-6-(2-pyridyl)- azabicyclo[4.1.0]heptan-3-yl]-(trifluoromethoxy)ethoxy]benzoic 3- [3-methoxy-4-[2- acidazabicyclo[4.1.0]heptane (trifluoromethoxy)ethoxy]phenyl]methanone[4-[(3,3- 4-[(3,3- 7,7-difluoro-6-(2-pyridyl)-difluorocyclobutyl)methoxy]- difluorocyclobutyl)methoxy]- 3-3-methoxy-phenyl]-[7,7- 3- azabicyclo[4.1.0]heptanedifluoro-6-(2-pyridyl)-3- methoxy-benzoic azabicyclo[4.1.0]heptan-3-acid yl]methanone [(3aR,7aR)-7a-(2,3- 3-methoxy-4-[(1S)-(3aR,7aR)-7a-(2,3- difluorophenyl)-3a,4,6,7- 2,2,2-trifluoro-1-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy]benzoic acid[1,3]dioxolo[4,5- [(1S)-2,2,2-trifluoro-1- c]pyridine methyl-ethoxy]phenyl]methanone [(3aR,7aR)-7a-(2,3- 3-methoxy-4-[(1R)-(3aR,7aR)-7a-(2,3- difluorophenyl)-3a,4,6,7- 2,2,2-trifluoro-1-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy]benzoic acid[1,3]dioxolo[4,5- [(1R)-2,2,2-trifluoro-1- c]pyridine methyl-ethoxy]phenyl]methanone [(3aR,7aR)-7a-(3- 4-(2-fluoro-2-(3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7- methyl-propoxy)-3-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-benzoictetrahydro-3aH- c]pyridin-5-yl]-[4-(2-fluoro-2- acid [1,3]dioxolo[4,5-methyl-propoxy)-3-methyl- c]pyridine phenyl]methanone [(3aR,7aR)-7a-(3-5-[(3,3- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-difluorocyclobutyl)methoxy]- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 6- tetrahydro-3aH-c]pyridin-5-yl]-[5-[(3,3- methoxy-pyridine- [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- 2-carboxylic acid c]pyridine 6-methoxy-2-pyridyl]methanone [(3aR,7aR)-7a-(3- 3-chloro-4-[2- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicfluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-chloro-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [3-chloro-4-[2- 3-chloro-4-[2-(1S,6R)-6-(2-pyridyl)-8- (trifluoromethoxy)ethoxy]phenyl]-(trifluoromethoxy)ethoxy]benzoic oxa-3- [(1S,6R)-6-(2-pyridyl)-8- acidazabicyclo[4.2.0]octane oxa-3-azabicyclo[4.2.0]octan- 3-yl]methanone[3-chloro-4-[2- 3-chloro-4-[2- (1R,6R)-6-(2-pyridyl)-8-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoicoxa-3- [(1R,6R)-6-(2-pyridyl)-8- acid azabicyclo[4.2.0]octaneoxa-3-azabicyclo[4.2.0]octan- 3-yl]methanone [(3aR,7aR)-7a-(3-4-[2-(2,2- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-difluorocyclopropyl)ethoxy]- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[2-(2,2- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclopropyl)ethoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-[4- 6-methoxy-5-[2- (3aR,7aR)-7a-[4-(trifluoromethyl)-2-pyridyl]- (trifluoromethoxy)ethoxy]pyridine-(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- 2- pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- carboxylic acid tetrahydro-3aH-yl]-[6-methoxy-5-[2- [1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]-2-c]pyridine pyridyl]methanone [(3aR,7aR)-7a-[4- 3-methoxy-4-(3aR,7aR)-7a-[4- (trifluoromethyl)-2-pyridyl]- (3,3,3-(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- trifluoropropoxy)benzoicpyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methoxy-4-(3,3,3- [1,3]dioxolo[4,5-trifluoropropoxy)phenyl]methanone c]pyridine [(3aR,7aR)-7a-[4- 5-[(3,3-(3aR,7aR)-7a-[4- (trifluoromethyl)-2-pyridyl]-difluorocyclobutyl)methoxy]- (trifluoromethyl)-2- 3a,4,6,7-tetrahydro-6- pyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-pyridine-tetrahydro-3aH- yl]-[5-[(3,3- 2-carboxylic acid [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- c]pyridine 6-methoxy-2- pyridyl]methanone[(3aR,7aR)-7a-(3- 6-ethoxy-5-[2- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]pyridine-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-ethoxy-5- carboxylic acid [1,3]dioxolo[4,5-[2-(trifluoromethoxy)ethoxy]- c]pyridine 2-pyridyl]methanone[(3aR,7aR)-7a-[4- 3-chloro-4-[2- (3aR,7aR)-7a-[4-(trifluoromethyl)-2-pyridyl]- (trifluoromethoxy)ethoxy]benzoic(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- acid pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- tetrahydro-3aH- yl]-[3-chloro-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-[4- 3-methoxy-4-[2- (3aR,7aR)-7a-[4-(trifluoromethyl)-2-pyridyl]- (trifluoromethoxy)ethoxy]benzoic(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- acid pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- tetrahydro-3aH- yl]-[3-methoxy-4-[2-[1,3]dioxolo[4,5- (trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[3-chloro-4-[2- 3-chloro-4-[2- 7,7-difluoro-6-(2-pyridyl)-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoic 3-[7,7-difluoro-6-(2- acid azabicyclo[4.1.0]heptane pyridyl)-3-azabicyclo[4.1.0]heptan-3- yl]methanone [(3aR,7aR)-7a-(4-methoxy-2-5-[(3,3- (3aR,7aR)-7a-(4- pyridyl)-3a,4,6,7-tetrahydro-difluorocyclobutyl)methoxy]- methoxy-2-pyridyl)-[1,3]dioxolo[4,5-c]pyridin-5- 6- 4,5,6,7-tetrahydro-3aH- yl]-[5-[(3,3-methoxy-pyridine- [1,3]dioxolo[4,5- difluorocyclobutyl)methoxy]-2-carboxylic acid c]pyridine 6-methoxy-2- pyridyl]methanone[(3aR,7aR)-7a-(4-methoxy-2- 3-methoxy-4-[2- (3aR,7aR)-7a-(4-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicmethoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- acid4,5,6,7-tetrahydro-3aH- yl]-[3-methoxy-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine[(3aR,7aR)-7a-(4-methoxy-2- 3-chloro-4-[2- (3aR,7aR)-7a-(4-pyridyl)-3a,4,6,7-tetrahydro- (trifluoromethoxy)ethoxy]benzoicmethoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- acid4,5,6,7-tetrahydro-3aH- yl]-[3-chloro-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine [(3aR,7aR)-7a-(3-3-methoxy-4-[(1S)- (3aR,7aR)-7a-(3- chlorophenyl)-3a,4,6,7-2,2,2-trifluoro-1- chlorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methyl- tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy]benzoicacid [1,3]dioxolo[4,5- [(1S)-2,2,2-trifluoro-1- c]pyridine methyl-ethoxy]phenyl]methanone [(3aR,7aR)-7a-(3- 3-methoxy-4-[(1R)-(3aR,7aR)-7a-(3- chlorophenyl)-3a,4,6,7- 2,2,2-trifluoro-1-chlorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- methyl-tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy]benzoic acid[1,3]dioxolo[4,5- [(1R)-2,2,2-trifluoro-1- c]pyridine methyl-ethoxy]phenyl]methanone [(3aR,7aR)-7a-(3- 4-fluoro-3- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- methoxy-benzoic fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-(4-fluoro-3- [1,3]dioxolo[4,5- methoxy-phenyl)methanonec]pyridine [(3aR,7aR)-7a-(3- 4- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-(cyclobutylmethoxy)- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-3-methoxy- tetrahydro-3aH- c]pyridin-5-yl]-[4- benzoic acid[1,3]dioxolo[4,5- (cyclobutylmethoxy)-3- c]pyridinemethoxy-phenyl]methanone [(3aR,7aR)-7a-(3- 4-[(3- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- fluorocyclobutyl)methoxy]-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 3-methoxy-tetrahydro-3aH- c]pyridin-5-yl]-[4-[(3- benzoic acid [1,3]dioxolo[4,5-fluorocyclobutyl)methoxy]-3- c]pyridine methoxy-phenyl]methanone[(3aR,7aR)-7a-(3- 3-methoxy-4- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-(2,2,3,3-tetrafluoro- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 1-methyl- tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- propoxy)benzoic [1,3]dioxolo[4,5-(2,2,3,3-tetrafluoro-1-methyl- acid c]pyridine propoxy)phenyl]methanone[3-chloro-4-[2- 3-chloro-4-[2- (1S,6R)-6-(2-pyridyl)-3-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoicazabicyclo[4.1.0]heptane [(1S,6R)-6-(2-pyridyl)-3- acidazabicyclo[4.1.0]heptan-3- yl]methanone [(3aR,7aR)-7a-(3-3-methoxy-4-[2- (3aR,7aR)-7a-(3- fluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-[4- 4-[(3,3-(3aR,7aR)-7a-[4- (trifluoromethyl)-2-pyridyl]-difluorocyclobutyl)methoxy]- (trifluoromethyl)-2- 3a,4,6,7-tetrahydro-3- pyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoictetrahydro-3aH- yl]-[4-[(3,3- acid [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-(3,5- 4-[(3,3- (3aR,7aR)-7a-(3,5-difluorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-difluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aR,7aR)-7a-[4- 4-[2-(2,2- (3aR,7aR)-7a-[4-(trifluoromethyl)-2-pyridyl]- difluorocyclopropyl)ethoxy]-(trifluoromethyl)-2- 3a,4,6,7-tetrahydro- 3- pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoic tetrahydro-3aH-yl]-[4-[2-(2,2- acid [1,3]dioxolo[4,5- difluorocyclopropyl)ethoxy]-c]pyridine 3-methoxy-phenyl]methanone [(3aR,7aR)-7a-(6-chloro-4-3-methoxy-4-[2- (3aR,7aR)-7a-(6-chloro-4- methoxy-2-pyridyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic methoxy-2-pyridyl)-tetrahydro-[1,3]dioxolo[4,5- acid 4,5,6,7-tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aS)-7a-(3-3-fluoro-4-[2- (3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-fluoro-4-[2- [1,3]dioxolo[4,5-(trifluoromethoxy)ethoxy]phenyl]methanone c]pyridine [(3aS,7aS)-7a-(3-4-(2-fluoro-2- (3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7-methyl-propoxy)-3- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-(trifluoromethyl)benzoic tetrahydro-3aH- c]pyridin-5-yl]-[4-(2-fluoro-2-acid [1,3]dioxolo[4,5- methyl-propoxy)-3- c]pyridine(trifluoromethyl)phenyl]methanone [(3aS,7aS)-7a-(3- 3-(trifluoromethyl)-(3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7- 4-(3,3,3-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-trifluoropropoxy)benzoic tetrahydro-3aH- c]pyridin-5-yl]-[3- acid[1,3]dioxolo[4,5- (trifluoromethyl)-4-(3,3,3- c]pyridinetrifluoropropoxy)phenyl]methanone [(3aS,7aS)-7a-(3- 3-chloro-4-(2-(3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7- fluoro-2-methyl-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- propoxy)benzoictetrahydro-3aH- c]pyridin-5-yl]-[3-chloro-4- acid [1,3]dioxolo[4,5-(2-fluoro-2-methyl- c]pyridine propoxy)phenyl]methanone[(3aS,7aS)-7a-(3- 3-chloro-4-[2- (3aS,7aS)-7a-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicfluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-chloro-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aS)-7a-(3- 4-[(3,3-(3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7- difluorocyclobutyl)methoxy]-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[(3aS,7aS)-7a-(3- 3-methoxy-4-[2- (3aS,7aS)-7a-(3-fluorophenyl)-3a,4,6,7- (trifluoromethoxy)ethoxy]benzoicfluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aS,7aS)-7a-(3-6-methoxy-5-[[1- (3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7-(trifluoromethyl)cyclopropyl]methoxy]pyridine- fluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- 2- tetrahydro-3aH-c]pyridin-5-yl]-[6-methoxy-5- carboxylic acid [1,3]dioxolo[4,5- [[1-c]pyridine (trifluoromethyl)cyclopropyl]methoxy]- 2- pyridyl]methanone[(3aS,7aS)-7a-(3- 3-methoxy-4- (3aS,7aS)-7a-(3- fluorophenyl)-3a,4,6,7-(2,2,2-trifluoro-1- fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5-methyl- tetrahydro-3aH- c]pyridin-5-yl]-[3-methoxy-4- ethoxy)benzoicacid [1,3]dioxolo[4,5- (2,2,2-trifluoro-1-methyl- c]pyridineethoxy)phenyl]methanone [(3aR,7aR)-7a-(3- 4-[(3,3- (3aR,7aR)-7a-(3-fluorophenyl)-3a,4,6,7- difluorocyclobutyl)methylamino]-fluorophenyl)-4,5,6,7- tetrahydro-[1,3]dioxolo[4,5- 3- tetrahydro-3aH-c]pyridin-5-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methylamino]- acid c]pyridine 3-methoxy-phenyl]methanone [4-[(3,3- 4-[(3,3- (1R,6R)-6-(2-pyridyl)-8-difluorocyclobutyl)methoxy]- difluorocyclobutyl)methoxy]- oxa-3-3-methoxy-phenyl]-[(1R,6R)- 3- azabicyclo[4.2.0]octane6-(2-pyridyl)-8-oxa-3- methoxy-benzoic azabicyclo[4.2.0]octan-3- acidyl]methanone [6-methoxy-5-(2,2,3,3- 6-methoxy-5-(1R,6R)-6-(2-pyridyl)-8- tetrafluoropropoxy)-2- (2,2,3,3- oxa-3-pyridyl]-[(1R,6R)-6-(2- tetrafluoropropoxy)pyridine-azabicyclo[4.2.0]octane pyridyl)-8-oxa-3- 2- azabicyclo[4.2.0]octan-3-carboxylic acid yl]methanone [3-chloro-4-[(3,3- 3-chloro-4-[(3,3-(1R,6R)-6-(2-pyridyl)-8- difluorocyclobutyl)methoxy]phenyl]-difluorocyclobutyl)methoxy]benzoic oxa-3- [(1R,6R)-6-(2- acidazabicyclo[4.2.0]octane pyridyl)-8-oxa-3- azabicyclo[4.2.0]octan-3-yl]methanone [3-chloro-4-[[1- 3-chloro-4-[[1- (1R,6R)-6-(2-pyridyl)-8-(trifluoromethyl)cyclopropyl]methoxy]phenyl]-(trifluoromethyl)cyclopropyl]methoxy]benzoic oxa-3- [(1R,6R)-6- acidazabicyclo[4.2.0]octane (2-pyridyl)-8-oxa-3- azabicyclo[4.2.0]octan-3-yl]methanone [3-methyl-4-[2- 3-methyl-4-[2- (1R,6R)-6-(2-pyridyl)-8-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoicoxa-3- [(1R,6R)-6-(2-pyridyl)-8- acid azabicyclo[4.2.0]octaneoxa-3-azabicyclo[4.2.0]octan- 3-yl]methanone [4-(2-fluoro-2-methyl-4-(2-fluoro-2- (1R,6R)-6-(2-pyridyl)-8- propoxy)-3- methyl-propoxy)-3-oxa-3- (trifluoromethyl)phenyl]- (trifluoromethyl)benzoicazabicyclo[4.2.0]octane [(1R,6R)-6-(2-pyridyl)-8-oxa- acid3-azabicyclo[4.2.0]octan-3- yl]methanone [(3aR,7aR)-7a-[4- 4-[(3,3-(3aR,7aR)-7a-[4- (trifluoromethyl)-2-pyridyl]-difluorocyclopentyl)methoxy]- (trifluoromethyl)-2- 3a,4,6,7-tetrahydro-3- pyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- methoxy-benzoictetrahydro-3aH- yl]-[4-[(3,3- acid [1,3]dioxolo[4,5-difluorocyclopentyl)methoxy]- c]pyridine 3-methoxy- phenyl]methanone[(3aR,7aR)-7a-(4-methoxy-2- 4-[(3,3- (3aR,7aR)-7a-(4-pyridyl)-3a,4,6,7-tetrahydro- difluorocyclobutyl)methoxy]-methoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5- 3-4,5,6,7-tetrahydro-3aH- yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone[3-chloro-4-[2- 3-chloro-4-[2- (1R,6R)-6-(2-pyridyl)-8-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoicoxa-3- [(1R,6R)-6-(2-pyridyl)-8- acid azabicyclo[4.2.0]octaneoxa-3-azabicyclo[4.2.0]octan- 3-yl]methanone [3-chloro-4-[2-3-chloro-4-[2- (1S,6S)-6-(2-pyridyl)-8-(trifluoromethoxy)ethoxy]phenyl]- (trifluoromethoxy)ethoxy]benzoicoxa-3- [(1S,6S)-6-(2-pyridyl)-8- acid azabicyclo[4.2.0]octaneoxa-3-azabicyclo[4.2.0]octan- 3-yl]methanone [(3aR,7aR)-7a-[4-3-methoxy-4-[[1- (3aR,7aR)-7a-[4- (trifluoromethyl)-2-pyridyl]-(trifluoromethyl)cyclopropyl]methoxy]benzoic (trifluoromethyl)-2-3a,4,6,7-tetrahydro- acid pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- tetrahydro-3aH- yl]-[3-methoxy-4-[[1-[1,3]dioxolo[4,5- (trifluoromethyl)cyclopropyl]methoxy]phenyl]methanonec]pyridine [(3aR,7aR)-7a-[4- 3-methoxy-4- (3aR,7aR)-7a-[4-(trifluoromethyl)-2-pyridyl]- (2,2,3,3- (trifluoromethyl)-2-3a,4,6,7-tetrahydro- tetrafluoropropoxy)benzoic pyridyl]-4,5,6,7-[1,3]dioxolo[4,5-c]pyridin-5- acid tetrahydro-3aH-yl]-[3-methoxy-4-(2,2,3,3- [1,3]dioxolo[4,5-tetrafluoropropoxy)phenyl]methanone c]pyridine [(3aR,7aR)-7a-(3,5-3-methoxy-4-[2- (3aR,7aR)-7a-(3,5- difluorophenyl)-3a,4,6,7-(trifluoromethoxy)ethoxy]benzoic difluorophenyl)-4,5,6,7-tetrahydro-[1,3]dioxolo[4,5- acid tetrahydro-3aH-c]pyridin-5-yl]-[3-methoxy-4- [1,3]dioxolo[4,5- [2- c]pyridine(trifluoromethoxy)ethoxy]phenyl]methanone [(3aR,7aR)-7a-(4-methoxy-2-3-methoxy-4- (3aR,7aR)-7a-(4- pyridyl)-3a,4,6,7-tetrahydro- (2,2,3,3-methoxy-2-pyridyl)- [1,3]dioxolo[4,5-c]pyridin-5-tetrafluoropropoxy)benzoic 4,5,6,7-tetrahydro-3aH-yl]-[3-methoxy-4-(2,2,3,3- acid [1,3]dioxolo[4,5-tetrafluoropropoxy)phenyl]methanone c]pyridine [(3aR,7aR)-7a-[4-4-(2-fluoro-2- (3aR,7aR)-7a-[4- (trifluoromethyl)-2-pyridyl]-methyl-propoxy)-3- (trifluoromethyl)-2- 3a,4,6,7-tetrahydro-methyl-benzoic pyridyl]-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- acidtetrahydro-3aH- yl]-[4-(2-fluoro-2-methyl- [1,3]dioxolo[4,5-propoxy)-3-methyl- c]pyridine phenyl]methanone[(3aR,7aR)-7a-(3-fluoro-2- 4-[(3,3- (3aR,7aR)-7a-(3-fluoro-2-pyridyl)-3a,4,6,7-tetrahydro- difluorocyclobutyl)methoxy]-pyridyl)-4,5,6,7- [1,3]dioxolo[4,5-c]pyridin-5- 3- tetrahydro-3aH-yl]-[4-[(3,3- methoxy-benzoic [1,3]dioxolo[4,5-difluorocyclobutyl)methoxy]- acid c]pyridine 3-methoxy-phenyl]methanone

(3-chloro-4-((3,3-difluorocyclobutyl)methoxy)phenyl)((3aR,7aR)-7a-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanoneStep 1:[(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone

A solution of 3-chloro-4-fluoro-benzoic acid (440 mg, 2.52 mmol) in DMF(7.2 mL) was treated with HATU (960 mg, 2.5 mmol) and the reactionmixture was allowed to stir for 5 min. A solution of(3aR,7aR)-7a-(pyridin-2-yl)hexahydro-[1,3]dioxolo[4,5-c]pyridine (500mg, 2.4 mmol) and triethylamine (2.5 mL, 14.5 mmol) in DMF (7.1 mL) wasadded to the mixture and the reaction mixture was stirred at rt for 2 h.The product was diluted with water and extracted with EtOAc (3×). Thecombined organics were washed with water, saturated aqueous NaCl, dried(Na₂SO₄), filtered and concentrated. Purification by flashchromatography (ethyl acetate-hexanes 10-50%) afforded[(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone(643 mg, 73%) which was used directly in the following reaction. ESI-MSm/z calc. 362.8. found 363.13 (M+1)⁺; Retention time: 1.27 min (3 minrun).

The following compounds were prepared using the procedure reportedabove.

Product Amine Benzoic Acid (3-chloro-4- [dimethylamino-3-chloro-4-fluoro- fluorophenyl)((3aR,7aR)-7a- (triazolo[5,4- benzoicacid (pyridin-2-yl)tetrahydro- b]pyridin-3- [1,3]dioxolo[4,5-c]pyridin-yloxy)methylene]- 5(6H)-yl)methanone dimethyl-ammonium (4-fluoro-3-[dimethylamino- 4-fluoro-3- (trifluoromethyl)phenyl)((3aR,7aR)-(triazolo[5,4- (trifluoromethyl)benzoic 7a-(pyridin-2-yl)tetrahydro-b]pyridin-3- acid [1,3]dioxolo[4,5-c]pyridin- yloxy)methylene]-5(6H)-yl)methanone dimethyl-ammonium (3-chloro-4- (3aR,7aR)-7a-(3-3-chloro-4-fluoro- fluorophenyl)((3aR,7aR)-7a-(3-fluorophenyl)hexahydro- benzoic acid fluorophenyl)tetrahydro-[1,3]dioxolo[4,5- [1,3]dioxolo[4,5-c]pyridin- c]pyridine5(6H)-yl)methanone

Step 2:(3-chloro-4-((3,3-difluorocyclobutyl)methoxy)phenyl)((3aR,7aR)-7a-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone

A solution of (3,3-difluorocyclobutyl)methanol (118 mg, 0.96 mmol) inDMF (1 mL) was treated with sodium hydride (42 mg, 1.06 mmol) and thereaction mixture was allowed to stir for 5 min.[(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-(3-chloro-4-fluoro-phenyl)methanone(175 mg, 0.48 mmol) was added as a solution in DMF (1 mL). The reactionmixture was allowed to stir at rt for 1 h, diluted with ethyl acetate(75 mL) and washed with saturated aqueous NaCl (1×75 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography: 4 gram silica gel column, 25-75% ethyl acetate/hexanegradient over 15 min to provide[(3aR,7aR)-7a-(2-pyridyl)-3a,4,6,7-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl]-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]phenyl]methanone(130 mg, 58%) as a thick oil. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H),7.75 (s, 1H), 7.62 (d, J=25.5 Hz, 2H), 7.44 (s, 1H), 7.26 (s, 1H), 6.93(d, J=8.2 Hz, 1H), 5.32 (s, 1H), 4.85 (s, 1H), 4.40 (s, 1H), 4.09 (d,J=5.2 Hz, 2H), 3.87 (t, J=53.2 Hz, 4H), 2.69 (dd, J=45.1, 10.2 Hz, 5H),2.35 (s, 1H), 2.09 (d, J=63.9 Hz, 1H). ESI-MS m/z calc. 464.1. found465.3 (M+1)⁺; Retention time: 1.57 min (3 min run).

The following compounds were prepared using the procedure reportedabove.

Product Precursor (3-chloro-4- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-(neopentyloxy)phenyl)((3aR,7aR)-7a-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5- (pyridin-2-yl)tetrahydro-c]pyridin-5(6H)-yl)methanone [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (3-chloro-4-(4,4,4-trifluoro-2-(3-chloro-4-fluorophenyl)((3aR,7aR)-7a-methylbutoxy)phenyl)((3aR,7aR)-7a-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5- (pyridin-2-yl)tetrahydro-c]pyridin-5(6H)-yl)methanone [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (3-chloro-4-((3,3- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-difluorocyclobutyl)methoxy)phenyl)((3aR,(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-7aR)-7a-(pyridin-2-yl)tetrahydro- c]pyridin-5(6H)-yl)methanone[1,3]dioxolo[4,5-c]pyridin-5(6H)- yl)methanone (3-chloro-4-((2,2-(3-chloro-4-fluorophenyl)((3aR,7aR)-7a-difluorocyclopropyl)methoxy)phenyl)((3aR,(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-7aR)-7a-(pyridin-2-yl)tetrahydro- c]pyridin-5(6H)-yl)methanone[1,3]dioxolo[4,5-c]pyridin-5(6H)- yl)methanone(4-(2-(tert-butoxy)ethoxy)-3- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-chlorophenyl)((3aR,7aR)-7a-(pyridin-2-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-yl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin- c]pyridin-5(6H)-yl)methanone5(6H)-yl)methanone (4-((2,2-difluorocyclopropyl)methoxy)-3- (4-fluoro-3-(trifluoromethyl)phenyl)((3aR,7aR)-7a-(trifluoromethyl)phenyl)((3aR,7aR)-7a- (pyridin-2-yl)tetrahydro-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-[1,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-yl)methanoneyl)methanone (4-(2,2-difluoropropoxy)-3- (4-fluoro-3-(trifluoromethyl)phenyl)((3aR,7aR)-7a-(trifluoromethyl)phenyl)((3aR,7aR)-7a- (pyridin-2-yl)tetrahydro-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-[1,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-yl)methanoneyl)methanone (4-((3,3-difluorocyclobutyl)methoxy)-3- (4-fluoro-3-(trifluoromethyl)phenyl)((3aR,7aR)-7a-(trifluoromethyl)phenyl)((3aR,7aR)-7a- (pyridin-2-yl)tetrahydro-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-[1,3]dioxolo[4,5-c]pyridin-5(6H)- c]pyridin-5(6H)-yl)methanoneyl)methanone ((3aR,7aR)-7a-(pyridin-2-yl)tetrahydro- (4-fluoro-3-[1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)(3-(trifluoromethyl)phenyl)((3aR,7aR)-7a- (trifluoromethyl)-4-((1,1,1-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5- trifluoropropan-2-c]pyridin-5(6H)-yl)methanone yl)oxy)phenyl)methanone(4-(cyclobutylmethoxy)-3- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-(3-methoxyphenyl)((3aR,7aR)-7a-(3-fluorophenyl)tetrahydro-[1,3]dioxolo[4,5- fluorophenyl)tetrahydro-c]pyridin-5(6H)-yl)methanone [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (4-(((1r,3R)-3- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-(3-fluorocyclobutyl)methoxy)-3- fluorophenyl)tetrahydro-[1,3]dioxolo[4,5-methoxyphenyl)((3aR,7aR)-7a-(3- c]pyridin-5(6H)-yl)methanonefluorophenyl)tetrahydro- [1,3]dioxolo[4,5-c]pyridin-5(6H)- yl)methanone(3-chloro-4-(2-(2,2,2- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-trifluoroethoxy)ethoxy)phenyl)((3aR,7aR)-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5- 7a-(pyridin-2-yl)tetrahydro-c]pyridin-5(6H)-yl)methanone [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (3-chloro-4-(2,2,3,3-(3-chloro-4-fluorophenyl)((3aR,7aR)-7a-tetrafluoropropoxy)phenyl)((3aR,7aR)-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5- 7a-(pyridin-2-yl)tetrahydro-c]pyridin-5(6H)-yl)methanone [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (3-chloro-4-(2,2- (3-chloro-4-fluorophenyl)((3aR,7aR)-7a-difluoropropoxy)phenyl)((3aR,7aR)-7a-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5- (pyridin-2-yl)tetrahydro-c]pyridin-5(6H)-yl)methanone [1,3]dioxolo[4,5-c]pyridin-5(6H)-yl)methanone (3-chloro-4-((1,1,1-trifluoropropan-2-(3-chloro-4-fluorophenyl)((3aR,7aR)-7a-yl)oxy)phenyl)((3aR,7aR)-7a-(pyridin-2-(pyridin-2-yl)tetrahydro-[1,3]dioxolo[4,5-yl)tetrahydro-[1,3]dioxolo[4,5-c]pyridin- c]pyridin-5(6H)-yl)methanone5(6H)-yl)methanone

Table 3 below recites the analytical data for the compounds of Table 1.

TABLE 3 Cmpd. LC/MS LC/RT No. M + 1 min NMR 1 479.00 1.52 ¹H NMR (400MHz, CDCl₃) δ 8.41 (d, J = 4.3 Hz, 1H), 7.57-7.44 (m, 1H), 7.35 (dt, J =8.4, 4.2 Hz, 1H), 7.19-6.98 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 5.34(broad s, 1H), 4.93 (broad s, 1H), 4.68 (broad s, 1H), 4.38 (broad m,1H), 4.08 (d, J = 6.4 Hz, 2H), 4.02 (broad s, 1H), 3.88 (s, 3H), 3.77(broad s, 1H), 3.49 (broad m, 1H), 2.91-2.62 (m, 3H), 2.60-2.42 (m, 2H),2.33 (broad m, 2H). 2 483.20 1.94 3 501.10 1.15 4 504.50 1.97 ¹H NMR(400 MHz, CDCl₃) δ 7.11 (broad s, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H),6.96-6.87 (m, 3H), 6.76 (tt, J = 8.7, 2.3 Hz, 1H), 5.31 (s, 1H), 4.85(s, 1H), 4.42-4.25 (m, 4H), 4.2-4.0 (broad d, 2H), 3.90 (s, 3H), 3.72(broad s, 3H), 2.32-1.90 (broad m, 2H). 5 384.40 1.68 6 437.25 1.52 7432.50 1.54 8 428.32 1.46 9 361.40 0.90 10 337.40 1.89 11 326.11 1.82 12470.40 1.60 ¹H NMR (400 MHz, MeOD) δ 9.11-8.93 (m, 2H), 7.80-7.60 (m,1H), 7.19-7.00 (m, 3H), 5.38 (s, 1H), 4.96 (s, 1H), 4.54 (s, 1H),4.40-4.35 (m, 2H), 4.30 (d, J = 4.0 Hz, 2H), 4.09 (d, J = 14.4 Hz, 1H),3.88 (s, 3H), 3.87-3.76 (m, 2H), 3.70 (s, 1H), 2.67-2.16 (m, 2H). 13366.50 1.95 ¹H NMR (400 MHz, MeOD) δ 7.47-7.22 (m, 7H), 6.99 (t, J = 9.1Hz, 1H), 4.72-4.54 (m, 2H), 4.46-4.03 (m, 2H), 3.99-3.74 (m, 2H), 3.66(dd, J = 25.7, 12.9 Hz, 1H), 3.09 (t, J = 15.9 Hz, 1H), 2.57-2.25 (m,1H), 2.21 (d, J = 7.8 Hz, 3H), 1.34 (d, J = 5.8 Hz, 6H). 14 323.13 1.5415 384.13 1.69 16 354.16 2.00 17 439.30 1.39 18 351.18 2.07 19 354.162.04 20 320.12 1.77 21 351.18 1.98 22 439.30 1.39 23 431.23 1.30 24437.25 1.52 25 413.10 1.15 26 397.12 1.68 27 416.40 1.68 28 348.17 1.6829 336.40 1.59 30 419.26 1.33 31 419.26 1.33 32 484.30 1.88 33 345.501.42 34 445.50 1.18 35 361.16 1.91 36 430.28 1.75 37 368.16 1.71 38448.28 1.76 39 475.20 1.71 40 471.00 1.18 41 499.50 1.09 42 428.28 1.4543 361.25 1.33 44 398.40 1.79 ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.19 (m,4H), 7.02-6.94 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 3.82 (s,2H), 3.45 (s, 1H), 2.28 (s, 3H), 2.14 (s, 2H), 1.74 (s, 2H), 1.38 (s,6H), 1.04 (s, 1H), 0.88 (t, J = 5.3 Hz, 1H). 45 382.29 1.51 46 472.301.45 47 448.31 1.76 48 484.26 1.88 49 382.29 1.50 50 453.30 1.32 51466.30 1.87 52 421.20 1.80 53 430.29 1.61 54 466.40 1.87 55 451.90 1.4256 367.50 1.58 57 354.50 1.69 58 430.29 1.61 59 463.00 1.24 60 397.191.65 61 467.40 1.41 62 463.00 1.24 ¹H NMR (400 MHz, MeOD) δ 7.82 (d, J =3.3 Hz, 1H), 7.58 (d, J = 3.3 Hz, 1H), 7.29-7.34 (m, 2H), 7.20 (t, J =8.4 Hz, 1H), 5.34 (s, 1H), 4.99 (s, 1H), 4.54-4.25 (m, 5H), 4.07-3.53(m, 4H), 2.55-2.02 (m, 2H). 63 429.40 1.69 64 467.20 0.96 ¹H NMR (400MHz, C₆D₆) δ 8.53 (s, 1H), 7.21-7.04 (m, 3H), 6.78-6.65 (m, J = 7.7 Hz,2H), 6.57 (d, J = 8.1 Hz, 1H), 4.15-3.91 (m, 4H), 3.86 (d, J = 8.2 Hz,1H), 3.81-3.70 (m, 4H), 3.68-3.58 (m, 2H), 3.37 (s, 3H), 3.18-2.95 (m, J= 29.0, 16.9 Hz, 2H), 2.27-1.98 (m, J = 53.8, 18.8 Hz, 2H). 65 408.301.85 66 467.30 1.35 67 418.30 1.63 68 469.10 1.40 ¹H NMR (400 MHz, DMSO)δ 8.59 (d, J = 4.2 Hz, 1H), 7.85 (td, J = 7.8, 1.7 Hz, 1H), 7.61 (d, J =7.9 Hz, 1H), 7.40-7.26 (m, 1H), 7.06 (d, J = 23.8 Hz, 3H), 5.31 (s, 1H),4.73 (s, 1H), 4.41 (dd, J = 5.3, 3.0 Hz, 2H), 4.33 (s, 1H), 4.29-4.25(m, 2H), 3.96-3.83 (m, 1H), 3.80 (s, 3H), 3.73 (d, J = 13.9 Hz, 1H),3.62 (dd, J = 6.8, 4.7 Hz, 1H), 3.55-3.45 (m, 1H), 2.30 (d, J = 14.7 Hz,1H), 2.04 (d, J = 14.7 Hz, 1H). 69 461.30 1.50 70 429.40 1.68 71 430.281.74 ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.36 (m, 4H), 7.36-7.28 (m, 1H),7.11 (s, 1H), 7.07 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H),5.30 (s, 1H), 4.87 (s, 1H), 4.27 (s, 1H), 4.03 (t, J = 14.4 Hz, 2H),3.90 (d, J = 8.6 Hz, 3H), 3.70 (s, 3H), 2.13 (s, 2H), 1.62 (s, 1H), 1.52(d, J = 21.4 Hz, 6H). 72 453.30 1.40 73 412.32 1.57 74 435.50 171.10 75412.29 1.57 76 361.40 1.34 77 382.40 1.96 78 489.20 1.60 ¹H NMR (400MHz, CDCl₃) δ 7.27 (d, J = 9.7 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 8.2Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.32 (s, 1H), 4.98 (s, 1H), 4.40 (s,1H), 4.36-4.24 (m, 4H), 4.01 (s, 2H), 3.90 (s, 4H), 3.71 (s, 2H), 2.88(s, 3H), 2.58 (s, 2H), 2.18 (s, 1H). 79 350.30 2.27 80 525.20 2.22 81382.30 1.96 82 421.29 1.67 83 420.15 2.03 84 485.00 1.24 85 475.27 1.5686 475.23 1.56 87 577.00 1.48 88 490.20 1.60 89 483.70 1.26 90 461.401.36 91 412.50 1.73 92 469.10 1.37 ¹H NMR (400 MHz, DMSO) δ 8.64-8.55(m, 1H), 7.86 (td, J = 7.8, 1.7 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.35(ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (s, 1H), 7.04 (s, 2H), 5.32 (s,1H), 4.87-4.69 (m, 1H), 4.42 (dd, J = 5.3, 3.1 Hz, 2H), 4.34 (bs, 1H),4.31-4.23 (m, 2H), 4.17-3.85 (m, 1H), 3.81 (s, 3H), 3.74 (d, J = 13.5Hz, 1H), 3.68-3.57 (m, 1H), 3.57-3.45 (m, 1H), 2.37-2.21 (m, 1H),2.13-1.98 (m, 1H). 93 487.30 1.53 ¹H NMR (400 MHz, CDCl₃) δ 8.60 (s,1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.12 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H),6.92 (d, J = 8.2 Hz, 1H), 5.39 (s, 1H), 5.05 (s, 1H), 4.67 (s, 2H), 4.32(tt, J = 8.8, 2.7 Hz, 4H), 4.08 (s, 1H), 3.96-3.69 (m, 5H), 3.62 (s,1H), 2.25 (d, J = 60.2 Hz, 2H). 94 503.50 1.26 95 415.20 1.45 ¹H NMR(400 MHz, DMSO) δ 8.60 (d, J = 4.0 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz,1H), 7.61 (d, J = 7.9 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H),7.30 (s, 2H), 7.05-6.94 (m, 1H), 5.30 (s, 1H), 4.73 (bs, 1H), 4.31 (bs,1H), 4.05 (d, J = 19.6 Hz, 2H), 3.95-3.81 (m, 1H), 3.74 (d, J = 13.1 Hz,1H), 3.67-3.42 (m, 2H), 2.38-2.23 (m, 1H), 2.22 (s, 3H), 2.14-1.89 (m, J= 17.1, 13.4 Hz, 1H), 1.46 (d, J = 21.4 Hz, 6H). 96 488.30 1.54 97421.25 1.67 98 366.17 1.97 99 486.30 1.84 ¹H NMR (400 MHz, CDCl₃) δ 7.36(dd, J = 8.5, 5.3 Hz, 2H), 7.09 (dd, J = 16.0, 7.5 Hz, 4H), 6.92 (d, J =7.9 Hz, 1H), 5.30 (s, 1H), 4.85 (s, 1H), 4.32 (dd, J = 7.7, 4.9 Hz, 4H),4.07 (s, 1H), 3.90 (s, 3H), 3.71 (s, 3H), 2.09 (s, 1H), 1.62 (s, 2H).100 433.40 1.64 ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 4.6 Hz, 1H), 7.47(ddd, J = 10.9, 8.3, 1.2 Hz, 1H), 7.39-7.27 (m, 3H), 6.80 (d, J = 8.9Hz, 1H), 5.31 (broad s, 1H), 4.91 (broad s, 1H), 4.66 (broad s, 1H),4.43-4.02 (m, 1H), 3.96 (d, J = 16.4 Hz, 3H, overlapped with broad s,1H), 3.79 (broad m, 1H), 3.50 (broad s, 1H), 2.28 (s, 3H, overlappedwith broad m, 2H), 1.55 (s, 3H), 1.50 (s, 3H). 101 437.20 0.84 ¹H NMR(400 MHz, DMSO-d6) δ 8.45 (d, J = 4.4 Hz, 1H), 7.71 (td, J = 7.7, 1.9Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.16 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H),7.05-7.00 (m, 2H), 6.95 (dd, J = 8.1, 1.9 Hz, 1H), 4.45-4.38 (m, 2H),4.31-4.24 (m, 2H), 3.90 (br s, 1H), 3.79 (s, 3H), 3.74 (br s, 1H), 3.46(br s, 1H), 3.28 (br s, 1H), 2.59 (br s, 1H), 2.10 (s, 1H), 1.70 (s,1H), 1.28 (dd, J = 9.1, 4.4 Hz, 1H), 1.05 (br s, 1H). 102 452.10 1.81 ¹HNMR (400 MHz, CDCl₃) δ 7.44-7.36 (m, 4H), 7.36-7.28 (m, 1H), 7.13 (s,1H), 7.09 (dd, J = 8.2, 1.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.31 (s,1H), 4.87 (s, 1H), 4.28 (t, J = 6.9 Hz, 3H), 4.07 (s, 1H), 3.90 (s, 3H),3.77 (d, J = 49.0 Hz, 3H), 2.70 (qt, J = 10.6, 7.0 Hz, 2H), 2.21 (d, J =29.3 Hz, 2H). 103 504.30 1.69 104 396.21 1.63 105 503.00 1.26 106 439.201.43 107 470.19 1.36 108 487.10 1.49 109 432.28 1.90 110 435.20 1.47 111476.20 1.59 112 499.30 1.12 ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, J = 6.4Hz, 1H), 7.47 (s, 1H), 7.21 (d, J = 5.9 Hz, 1H), 7.15 (s, 1H), 7.13-7.07(m, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.39 (s, 1H), 4.99 (s, 1H), 4.71 (s,1H), 4.62 (d, J = 15.1 Hz, 1H), 4.38-4.21 (m, 4H), 4.14 (s, 3H), 3.97(dd, J = 15.1, 2.1 Hz, 1H), 3.90 (s, 3H), 3.84-3.79 (m, 1H), 3.08-2.86(m, 1H), 2.21 (d, J = 14.6 Hz, 1H), 1.69-1.61 (m, 1H). 113 350.30 1.69114 380.20 1.78 115 380.50 1.89 116 457.50 1.54 117 452.20 1.84 118490.20 1.69 119 431.50 1.96 120 414.50 1.91 ¹H NMR (400 MHz, CDCl₃) δ7.44-7.36 (m, 4H), 7.36-7.28 (m, 3H), 6.84-6.78 (m, 1H), 5.30 (s, 1H),4.87 (s, 1H), 4.25 (s, 1H), 3.98 (t, J = 15.7 Hz, 3H), 3.75 (s, 3H),2.28 (s, 3H), 2.16 (d, J = 36.8 Hz, 2H), 1.52 (d, J = 21.4 Hz, 6H). 121431.20 1.75 122 486.50 1.85 ¹H NMR (400 MHz, CDCl₃) δ 7.36 (dd, J = 8.5,5.2 Hz, 2H), 7.09 (dd, J = 16.0, 7.5 Hz, 4H), 6.92 (d, J = 7.7 Hz, 1H),5.30 (s, 1H), 4.85 (s, 1H), 4.38-4.27 (m, 5H), 4.07 (s, 1H), 3.90 (s,3H), 3.71 (s, 3H), 2.09 (s, 1H), 1.61 (s, 2H). 123 509.00 1.25 124432.32 1.89 125 399.50 1.95 126 476.20 1.61 127 469.40 1.56 128 491.301.58 129 471.40 1.69 130 480.00 1.47 ¹H NMR (400 MHz, CDCl₃) 2conformers observed (ca. 30:70) δ 8.60 (br s, 1H), 7.87-7.72 (m, 1H),7.66 (dd, J = 22.8, 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26 (br m,1H), 7.13 (d, J = 8.0 Hz, 1H), 5.36 (s, 30% of 1H), 5.29 (s, 70% of 1H),4.95 (s, 30% of 1H), 4.84 (s, 70% of 1H), 4.60 (br m, 30% of 1H), 4.51(br m, 70% of 1H), 4.33-4.28 (m, 1H), 4.23-4.05 (m, 3H), 4.02 (s, 70% of3H), 3.97 (s, 30% of 3H), 3.94-3.69 (m, 2H), 2.44 (br m, 1H), 2.24-1.96(m, 1H), 1.21-1.08 (m, 2H), 0.97 (s, 2H). 131 486.23 1.89 ¹H NMR (400MHz, CDCl₃) δ 7.40 (s, 1H), 7.37-7.27 (m, 2H), 7.24 (dd, J = 5.2, 3.6Hz, 1H), 7.12 (s, 1H), 7.08 (dd, J = 8.2, 1.7 Hz, 1H), 6.90 (d, J = 8.2Hz, 1H), 5.31 (s, 1H), 4.85 (s, 1H), 4.28 (t, J = 6.9 Hz, 2H), 4.25-3.93(m, 2H), 3.90 (s, 3H), 3.85-3.54 (m, 3H), 2.70 (qt, J = 10.6, 7.0 Hz,2H), 2.32-1.92 (m, 2H). 132 482.20 1.33 ¹H NMR (400 MHz, CDCl₃) δ 7.52(d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H),7.11-6.83 (m, 3H), 4.59-3.90 (m, 8H), 3.88 (s, 3H), 3.81-3.40 (m, 6H),2.80-1.40 (m, 2H). 133 380.40 1.78 ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.22(m, 6H), 7.22-7.17 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 3.92 (s, 1H), 3.82(s, 2H), 3.49 (s, 2H), 2.28 (s, 3H), 2.14 (d, J = 41.4 Hz, 2H), 1.57 (d,J = 27.3 Hz, 2H), 1.38 (s, 6H), 1.08 (s, 1H), 0.89 (t, J = 5.2 Hz, 1H).134 351.40 1.77 135 451.40 1.45 136 434.40 2.06 137 490.20 1.67 138479.30 1.76 139 460.40 1.81 ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.37 (m, 4H),7.36-7.28 (m, 1H), 7.11 (broad s, 1H), 7.08 (dd, J = 8.2, 1.8 Hz, 1H),6.89 (d, J = 8.2 Hz, 1H), 5.30 (broad s, 1H), 4.87 (s, 1H), 4.27 (broadm, 1H), 4.08 (d, J = 6.3 Hz, 2H, overlapped with broad s, 1H), 3.88 (s,3H), 3.70 (broad s, 3H), 2.89-2.61 (m, 3H), 2.61-2.35 (m, 2H), 2.07 (d,broad m, 2H). 140 479.30 1.75 141 547.10 1.80 ¹H NMR (400 MHz, DMSO) δ7.83 (t, J = 7.8 Hz, 1H), 7.64 (dd, J = 10.5, 7.7 Hz, 2H), 7.09 (s, 1H),7.04 (s, 2H), 5.31 (s, 1H), 4.75 (s, 1H), 4.42 (dd, J = 5.3, 3.1 Hz,2H), 4.37-4.22 (m, 3H), 4.04-3.85 (m, 1H), 3.81 (s, 3H), 3.75-3.57 (m,2H), 3.55-3.43 (m, 1H), 2.37-2.17 (m, 1H), 2.15-1.97 (m, 1H). 142 459.401.88 143 329.12 1.50 144 473.30 1.78 145 491.20 1.69 146 465.20 1.56 ¹HNMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.75 (s, 1H), 7.62 (d, J = 25.5 Hz,2H), 7.44 (s, 1H), 7.26 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.32 (s, 1H),4.85 (s, 1H), 4.40 (s, 1H), 4.09 (d, J = 5.2 Hz, 2H), 3.87 (t, J = 53.2Hz, 4H), 2.69 (dd, J = 45.1, 10.2 Hz, 5H), 2.35 (s, 1H), 2.09 (d, J =63.9 Hz, 1H), 1.58 (s, 3H). 147 366.30 1.79 148 468.29 1.78 149 493.201.76 150 468.26 1.78 ¹H NMR (400 MHz, CDCl₃) δ 7.40 (dd, J = 7.6, 5.7Hz, 4H), 7.36-7.28 (m, 1H), 7.13 (s, 1H), 7.08 (dd, J = 8.2, 1.6 Hz,1H), 6.92 (d, J = 8.1 Hz, 1H), 5.30 (s, 1H), 4.87 (s, 1H), 4.37-4.26 (m,4H), 4.08 (s, 1H), 3.90 (s, 3H), 3.71 (s, 2H), 2.20 (d, J = 35.6 Hz,2H), 1.60 (s, 2H). 151 394.10 2.30 152 449.30 1.95 153 538.40 1.89 154483.20 1.29 155 503.20 1.95 156 457.40 1.54 157 473.10 1.54 ¹H NMR (400MHz, DMSO) δ 8.61 (d, J = 4.1 Hz, 1H), 7.89 (td, J = 7.8, 1.7 Hz, 1H),7.63 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.38(dd, J = 7.0, 5.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 5.31 (s, 1H), 4.73(s, 1H), 4.46 (dd, J = 5.5, 2.6 Hz, 2H), 4.40 (d, J = 4.6 Hz, 2H),4.37-4.29 (m, 1H), 3.89-3.71 (m, 2H), 3.55-3.46 (m, 2H), 2.36-2.21 (m,1H), 2.08-1.88 (m, 1H). 158 398.30 1.93 159 471.40 1.81 ¹H NMR (400 MHz,CDCl₃) δ 7.46-7.36 (m, 5H), 7.31 (ddd, J = 6.7, 5.5, 2.4 Hz, 1H),7.20-7.13 (m, 1H), 4.50-4.32 (m, 3H), 4.30 (dd, J = 5.3, 3.1 Hz, 2H),4.05 (d, J = 4.4 Hz, 4H), 3.98 (s, 1H), 3.96-3.88 (m, 1H), 3.84-3.61 (m,1H), 2.26 (ddd, J = 20.3, 12.1, 4.5 Hz, 1H), 2.20-2.10 (m, 1H). 160454.40 1.28 161 414.40 1.91 ¹H NMR (400 MHz, CDCl₃) δ 7.39 (t, J = 4.5Hz, 4H), 7.37-7.28 (m, 3H), 6.83-6.78 (m, 1H), 5.30 (s, 1H), 4.87 (s,1H), 4.29 (s, 1H), 3.96 (d, J = 16.4 Hz, 3H), 3.74 (s, 3H), 2.28 (s,3H), 2.12 (s, 2H), 1.52 (d, J = 21.4 Hz, 7H). 162 505.20 1.80 ¹H NMR(400 MHz, CDCl₃) δ 7.42 (d, J = 7.5 Hz, 2H), 7.20 (t, J = 21.1 Hz, 3H),5.30 (d, J = 28.2 Hz, 1H), 4.81 (d, J = 35.5 Hz, 1H), 4.39 (t, J = 39.8Hz, 5H), 4.17-3.60 (m, 7H), 2.18 (dd, J = 82.8, 67.7 Hz, 2H), 1.63 (s,1H). 163 504.30 1.87 ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.30 m, 1H), 7.11(s, 1H), 7.10-6.95 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 5.30 (br s, 1H),4.79 (br s, 1H), 4.35-4.20 (m, 5H), 4.05-3.92 (m, 1H), 3.89 (s, 3H),3.82-3.55 (m, 3H), 2.42-2.28 (m, 1H), 2.18-2.06 (m, 1H). 164 485.10 1.70165 453.10 1.53 166 475.10 1.51 167 459.30 1.76 ¹H NMR (400 MHz, CDCl₃)δ 7.81 (d, J = 3.2 Hz, 1H), 7.41-7.28 (m, 3H), 6.85-6.75 (m, 1H), 5.35(s, 1H), 5.06 (s, 1H), 4.33 (dd, J = 5.8, 3.3 Hz, 3H), 4.26-4.19 (m,2H), 3.98-3.60 (m, 3H), 2.52-2.21 (m, 6H). 168 459.30 1.76 169 537.231.87 170 486.23 1.99 171 380.40 1.77 172 498.30 1.93 173 490.20 1.98 174506.30 1.91 ¹H NMR (400 MHz, CDCl₃) δ 7.11 (s, 1H), 7.06 (dd, J = 8.2,1.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 3H), 6.80-6.72 (m, 1H), 5.29 (s, 0H),4.83 (s, 0H), 4.38-4.26 (m, 4H), 4.26-4.13 (m, 1H), 4.05 (s, 1H), 3.90(s, 3H), 3.72 (s, 3H), 2.10 (s, 2H). 175 495.00 1.50 176 494.23 1.93 177480.40 1.87 178 437.40 1.99 179 537.40 1.81 ¹H NMR (400 MHz, CDCl₃) δ8.76 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.55-7.41 (m, 1H), 7.22-7.03 (m,2H), 6.92 (d, J = 8.1 Hz, 1H), 5.36 (s, 1H), 4.88 (s, 1H), 4.54-4.24 (m,5H), 4.19-3.96 (m, 1H), 3.90 (s, 3H), 3.90-3.51 (m, 3H), 2.40-1.93 (m,2H). 180 479.00 1.60 ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.0 Hz, 1H),7.40-7.30-(m, 1H), 7.20-7.10 (m, 3H), 7.04-6.95 (m, 1H), 5.34 and 5.26(2 s, 30%:70%, total 1H), 4.93 and 4.85 (2 s, 30%:70%, total 1H), 4.44and 4.36 (2 t, J = 4.1 Hz, 30%:70%, total 1H), 4.17-3.51 (m, 9H),2.87-2.59 (m, 3H), 2.58-2.39 (m, 2H), 2.34-2.06 (m, 2H). 181 488.40 1.85¹H NMR (400 MHz, CDCl₃) δ 7.37 (td, J = 8.1, 5.9 Hz, 1H), 7.20-7.10 (m,3H), 7.07 (dd, J = 8.2, 1.9 Hz, 1H), 7.01 (td, J = 8.0, 2.2 Hz, 1H),6.92 (d, J = 8.2 Hz, 1H), 4.49-4.17 (m, 5H), 4.08 (s, 1H), 3.90 (s, 3H),3.71 (s, 3H), 2.05 (d, J = 35.4 Hz, 2H). 182 487.20 2.00 183 503.20 1.94184 496.31 1.87 ¹H NMR (400 MHz, CDCl₃) δ 7.38 (t, J = 7.0 Hz, 1H),7.21-7.09 (m, 3H), 7.07 (dd, J = 8.2, 1.9 Hz, 1H), 6.89 (d, J = 8.2 Hz,1H), 5.30 (broad s, 1H), 4.78 (broad s, 1H), 4.28 (broad s, 1H), 4.07(d, J = 6.3 Hz, 2H), 3.99 (broad s, 1H), 3.88 (s, 3H), 3.77 (broad s,3H), 2.88-2.58 (m, 3H), 2.58-2.42 (m, 2H), 2.36 (broad s, 1H), 2.11(broad s, 1H). 185 489.40 1.84 ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.32 (m,2H), 7.29-7.10 (m, 3H), 7.01 (dd, J = 9.4, 7.7 Hz, 1H), 6.30-5.92 (m,1H), 5.30 (d, J = 29.8 Hz, 1H), 4.88 (d, J = 27.8 Hz, 1H), 4.51-4.30 (m,3H), 4.14-3.88 (m, 6H), 3.82-3.57 (m, 1H), 2.18 (ddd, J = 23.1, 15.1,9.9 Hz, 2H). 186 504.24 1.83 187 488.25 1.93 188 487.30 1.86 ¹H NMR (400MHz, CDCl₃) δ 7.44 (d, J = 7.9 Hz, 1H), 7.36 (td, J = 8.0, 5.9 Hz, 1H),7.16 (dd, J = 10.5, 7.3 Hz, 3H), 7.05-6.97 (m, 1H), 5.30 (d, J = 30.4Hz, 1H), 4.89 (d, J = 28.6 Hz, 1H), 4.47-4.25 (m, 5H), 4.04 (s, 4H),3.96 (d, J = 14.8 Hz, 2H), 3.82-3.57 (m, 1H), 3.49 (s, 0H), 2.33-2.08(m, 2H), 1.59 (s, 1H). 189 489.40 1.88 190 483.20 1.92 ¹H NMR (400 MHz,DMSO) δ 7.80-7.71 (m, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 7.2Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.29 (s,1H), 4.76 (s, 1H), 4.49-4.42 (m, 2H), 4.33-4.26 (m, 2H), 4.23 (dt, J =9.7, 4.1 Hz, 1H), 3.86 (s, 3H), 3.82-3.70 (m, 1H), 3.70-3.59 (m, 1H),3.59-3.45 (m, 1H), 3.40-3.34 (m, 1H), 2.40-2.24 (m, 1H), 2.19 (s, 3H),2.07-1.78 (m, 1H). 191 421.20 1.91 192 499.20 1.78 193 478.30 1.86 ¹HNMR (400 MHz, CDCl₃) δ 7.37 (td, J = 8.1, 5.9 Hz, 1H), 7.13 (dd, J =12.9, 5.5 Hz, 3H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 7.01 (td, J = 8.3,2.4 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.31 (s, 1H), 4.86 (s, 1H), 4.24(s, 1H), 4.08 (d, J = 6.3 Hz, 3H), 3.88 (s, 3H), 3.72 (d, J = 14.5 Hz,2H), 3.49 (s, 0H), 2.85-2.62 (m, 3H), 2.58-2.40 (m, 2H), 2.09 (s, 2H),1.53 (d, J = 28.0 Hz, 1H). 194 467.20 1.50 ¹H NMR (400 MHz, DMSO) δ 7.74(t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.30 (s, 2H), 7.21 (d, J= 7.7 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.28 (s, 1H), 4.72 (s, 1H),4.50-4.39 (m, 2H), 4.39-4.20 (m, 3H), 4.20-3.79 (m, 1H), 3.78-3.67 (m,1H), 3.68-3.56 (m, 1H), 3.56-3.46 (m, 1H), 2.48 (s, 3H), 2.36-2.22 (m,1H), 2.19 (s, 3H), 2.14-1.86 (m, 1H). 195 436.30 2.11 196 505.50 1.84197 539.40 1.85 198 547.40 1.95 199 491.00 1.29 200 493.30 2.04 ¹H NMR(400 MHz, CDCl₃) δ 7.45 (d, J = 8.0 Hz, 1H), 7.43-7.32 (m, 1H), 7.15 (d,J = 7.1 Hz, 2H), 7.09 (t, J = 7.0 Hz, 1H), 7.05-6.95 (m, 1H), 5.30 (d, J= 31.1 Hz, 1H), 4.89 (d, J = 28.8 Hz, 1H), 4.40 (dt, J = 28.2, 4.1 Hz,1H), 4.08 (t, J = 7.0 Hz, 2H), 4.03 (s, 3H), 4.00-3.90 (m, 3H),3.86-3.48 (m, J = 16.2, 13.5, 5.4 Hz, 1H), 2.86-2.65 (m, 2H), 2.48-2.10(m, 5H), 2.06 (q, J = 6.4 Hz, 2H). 201 457.50 1.35 202 457.50 1.35 203491.40 1.12 204 543.40 1.91 205 453.50 1.54 206 437.10 1.49 207 467.501.58 208 449.30 1.11 209 456.40 0.91 210 445.50 0.92 211 477.00 1.79 212470.50 2.04 213 497.50 2.08 214 486.50 2.01 215 478.50 2.02 216 490.302.09 217 452.30 2.08 218 508.30 2.14 219 486.50 2.14 220 474.30 2.06 221533.40 1.70 222 529.00 1.85 223 519.20 1.62 ¹H NMR (400 MHz, CDCl₃) δ7.44 (d, J = 7.9 Hz, 1H), 7.36 (td, J = 8.0, 5.9 Hz, 1H), 7.20-7.12 (m,J = 8.0 Hz, 2H), 7.09 (t, J = 7.0 Hz, 1H), 7.04-6.96 (m, 1H), 5.30 (d, J= 31.5 Hz, 1H), 4.89 (d, J = 29.1 Hz, 1H), 4.52-4.22 (m, 1H), 4.13-4.04(m, 2H), 4.03 (s, 3H), 4.02-3.91 (m, 4H), 3.84-3.49 (m, 1H), 2.87-2.70(m, 1H), 2.68-2.47 (m, 3H), 2.41-2.01 (m, 6H). 224 493.20 1.53 ¹H NMR(400 MHz, CDCl₃) δ 7.42 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 14.0, 8.0 Hz,1H), 7.23-7.11 (m, 3H), 7.08-6.95 (m, 1H), 5.30 (d, J = 29.9 Hz, 1H),4.89 (d, J = 28.3 Hz, 1H), 4.40 (d, J = 27.3 Hz, 2H), 4.07 (s, 1H), 4.02(s, 3H), 3.96 (s, 2H), 3.86-3.53 (m, 1H), 2.81-2.35 (m, 5H), 2.35-2.07(m, 2H), 1.28 (d, J = 5.3 Hz, 3H). 225 496.40 1.72 ¹H NMR (400 MHz,CDCl₃) δ 7.13-7.00 (m, 2H), 6.96-6.84 (m, 3H), 6.76 (tt, J = 8.7, 2.3Hz, 1H), 5.31 (s, 1H), 4.85 (s, 1H), 4.37-4.13 (m, 1H), 4.12-3.95 (m,3H), 3.89 (s, 3H), 3.84-3.54 (m, 3H), 2.86-2.59 (m, 3H), 2.59-2.38 (m,2H), 2.35-1.81 (m, 2H). 226 529.40 1.73 ¹H NMR (400 MHz, CDCl₃) δ 8.76(d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.57-7.40 (m, 1H), 7.18-7.01 (m, 2H),6.89 (d, J = 8.1 Hz, 1H), 5.36 (s, 1H), 4.89 (s, 1H), 4.55-4.18 (m, 1H),4.16-4.09 (m, 1H), 4.08 (d, J = 6.3 Hz, 2H), 3.95-3.89 (m, 1H), 3.89 (s,3H), 3.88-3.60 (m, 2H), 2.87-2.60 (m, 3H), 2.60-2.40 (m, 2H), 2.40-2.07(m, 2H). 227 479.30 1.82 228 486.50 1.77 ¹H NMR (400 MHz, CDCl₃) δ 7.37(td, J = 8.1, 6.0 Hz, 1H), 7.13 (d, J = 3.4 Hz, 3H), 7.08 (d, J = 8.2Hz, 1H), 7.05-6.97 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.31 (s, 1H), 4.86(s, 1H), 4.29 (tt, J = 90.1, 45.2 Hz, 6H), 3.90 (s, 3H), 3.74 (s, 3H),2.11 (s, 2H). 229 491.50 1.88 230 491.50 1.92 231 441.50 1.99 232 455.702.15 233 465.20 1.41 ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 7.8 Hz, 1H),7.36 (dd, J = 14.0, 7.9 Hz, 1H), 7.15 (d, J = 7.4 Hz, 2H), 6.99 (dt, J =14.4, 7.5 Hz, 2H), 5.30 (d, J = 29.9 Hz, 1H), 4.89 (d, J = 28.3 Hz, 1H),4.69 (s, 1H), 4.39 (dt, J = 6.8, 3.7 Hz, 1H), 4.05 (s, 3H), 4.11-3.89(m, 3H), 3.83-3.54 (m, 1H), 3.21-3.05 (m, 2H), 2.95-2.76 (m, 2H),2.34-2.08 (m, 2H). 234 503.20 1.52 ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.30(m, 2H), 7.30-7.21 (m, 1H), 7.15 (d, J = 7.5 Hz, 2H), 7.01 (dd, J = 9.6,7.7 Hz, 1H), 6.38-5.94 (m, 1H), 5.30 (d, J = 28.7 Hz, 1H), 4.88 (d, J =27.5 Hz, 1H), 4.81-4.65 (m, 1H), 4.39 (dt, J = 33.8, 4.0 Hz, 1H),4.10-4.04 (m, 1H), 4.04 (s, 3H), 4.00-3.87 (m, 2H), 3.82-3.51 (m, 1H),2.19 (ddd, J = 23.4, 15.0, 10.0 Hz, 2H), 1.48 (d, J = 5.8 Hz, 3H). 235493.10 1.64 ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.0 Hz, 1H), 7.36(td, J = 8.0, 5.8 Hz, 1H), 7.23-7.08 (m, 3H), 7.00 (td, J = 7.8, 7.3,2.1 Hz, 1H), 5.30 (d, J = 31.2 Hz, 1H), 4.89 (d, J = 28.9 Hz, 1H),4.53-4.26 (m, 1H), 4.13-3.88 (m, 7H), 3.83-3.51 (m, 1H), 2.82-2.64 (m,1H), 2.37 (dd, J = 22.7, 11.8 Hz, 1H), 2.32-1.89 (m, 5H), 1.78-1.57 (m,3H). 236 505.30 2.01 237 505.30 1.98 238 441.30 1.43 239 502.00 7.17 240460.00 6.71 241 442.00 7.13 242 376.00 1.57 243 ¹H NMR (400 MHz, CDCl₃)δ 7.40 (s, 1H), 7.37-7.21 (m, 3H), 7.13 (s, 1H), 7.03 (s, 2H), 5.30 (s,1H), 4.85 (s, 1H), 4.61 (dt, J = 12.7, 6.3 Hz, 1H), 4.48-3.98 (m, 2H),3.90 (s, 3H), 3.87-3.39 (m, 3H), 2.35-1.88 (m, 2H), 1.52 (d, J = 6.5 Hz,3H). 244 ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H), 7.36-7.27 (m, 2H),7.27-7.21 (m, 1H), 7.13 (s, 1H), 7.03 (s, 2H), 5.30 (s, 1H), 4.84 (s,1H), 4.60 (hept, J = 6.4 Hz, 1H), 4.42-3.96 (m, 2H), 3.90 (s, 3H),3.84-3.48 (m, 3H), 2.35-1.89 (m, 2H), 1.52 (d, J = 6.5 Hz, 3H). 245503.20 1.26 246 492.40 1.13 247 477.00 5.84 248 541.40 1.94 249 501.502.08 250 530.40 1.92 251 521.40 1.85 ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d,J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.46 (dd, J = 5.0, 1.0 Hz, 1H), 7.31-6.98(m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.36 (s, 1H), 4.89 (s, 1H), 4.56-4.33(m, 1H), 4.28 (t, J = 6.9 Hz, 2H), 4.17-4.01 (m, 1H), 3.90 (s, 3H),4.02-3.50 (m, 3H), 2.70 (qt, J = 10.6, 6.9 Hz, 2H), 2.25 (d, J = 43.9Hz, 2H). 252 478.00 1.80 253 457.50 1.44 254 515.40 1.78 255 490.30 1.99256 432.50 1.88 ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.26 (m, 3H), 7.22-7.06(m, 2H), 7.08-6.93 (m, 1H), 6.87-6.72 (m, 1H), 5.31 (broad s, 1H), 4.86(broad s, 1H), 4.22 (broad s, 1H), 3.96 (d, J = 16.4 Hz, 2H, overlappedwith broad s, 1H), 3.72 (broad s, 3H), 2.28 (s, 3H), 2.25-1.87 (m, 2H),1.55 (s, 3H), 1.50 (s, 3H). 257 488.10 1.63 ¹H NMR (400 MHz, CDCl₃) δ7.38 (t, J = 6.9 Hz, 1H), 7.21-7.09 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H),5.30 (s, 1H), 4.77 (bs, 1H), 4.61 (dt, J = 12.7, 6.3 Hz, 1H), 4.28 (bs,1H), 4.04-3.92 (m, 1H), 3.89 (s, 3H), 3.87-3.67 (m, 3H), 2.45-2.26 (m,1H), 2.24-2.08 (m, 1H), 1.51 (d, J = 6.5 Hz, 3H). 258 488.10 1.85 ¹H NMR(400 MHz, CDCl₃) δ 7.38 (t, J = 7.0 Hz, 1H), 7.20-7.08 (m, 3H),7.07-6.95 (m, 2H), 5.30 (s, 1H), 4.77 (s, 1H), 4.60 (dt, J = 12.8, 6.4Hz, 1H), 4.28 (bs, 1H), 4.03-3.92 (m, 1H), 3.89 (s, 3H), 3.86-3.63 (m,3H), 2.44-2.28 (m, 1H), 2.27-2.08 (m, 1H), 1.52 (d, J = 6.5 Hz, 3H). 259465.00 1.38 260 473.00 1.37 261 442.50 1.80 262 507.40 1.86 263 489.201.91 264 471.40 1.88 265 479.00 1.83 266 437.20 0.83 ¹H NMR (400 MHz,DMSO-d6) δ 8.45 (d, J = 3.5 Hz, 1H), 7.71 (td, J = 7.8, 1.9 Hz, 1H),7.34 (d, J = 8.1 Hz, 1H), 7.16 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H),7.05-7.00 (m, 2H), 6.95 (dd, J = 8.2, 1.9 Hz, 1H), 4.46-4.37 (m, 2H),4.31-4.23 (m, 2H), 3.89 (br s, 1H), 3.79 (s, 3H), 3.61 (br s, 1H), 3.53(br s, 1H), 3.28 (br s, 1H), 2.59 (br s, 1H), 2.10 (br s, 1H), 1.70 (brs, 1H), 1.28 (dd, J = 8.9, 4.4 Hz, 1H), 1.05 (br s, 1H), 1.95-1.55 (m,1H). 267 530.00 1.48 268 497.00 1.48 269 517.00 1.52 270 513.00 1.56 271515.00 1.51 272 538.24 1.85 273 521.24 1.90 274 521.24 1.85 275 529.301.91 276 467.20 0.98 277 481.20 1.15 278 467.20 0.98 279 481.00 1.42 280499.00 1.46 281 497.00 1.45 282 488.25 1.83 283 502.22 1.91 284 445.001.50 ¹H NMR (400 MHz, MeOD) δ 7.45-7.37 (m, 1H), 7.33-7.21 (m, 4H),7.07-6.98 (m, 1H), 4.45-4.30 (m, 1H), 4.25-4.15 (m, 1H), 4.07-3.92 (m,6H), 3.92-3.79 (m, 1H), 3.71 (dd, J = 8.3, 3.0 Hz, 1H), 2.91-2.67 (m,1H), 2.34-1.85 (m, 8H). 285 437.20 0.85 286 488.10 1.93 287 488.40 1.83288 496.40 1.89 289 505.30 1.89 290 477.30 1.80 291 485.40 1.76 292494.40 1.76 293 493.40 1.74 294 474.10 1.53 295 473.10 1.90 296 459.162.06 297 438.10 2.01 298 446.20 1.96 299 455.20 1.96 300 454.10 1.94 301458.10 2.08 302 470.40 1.81 ¹H NMR (400 MHz, CDCl₃) δ 7.40 (dd, J = 7.7,5.8 Hz, 4H), 7.36-7.28 (m, 1H), 7.13 (s, 1H), 7.08 (dd, J = 8.2, 1.8 Hz,1H), 6.92 (d, J = 8.2 Hz, 1H), 4.55-3.96 (m, 6H), 3.90 (s, 3H), 3.71 (s,3H), 2.09 (d, J = 38.5 Hz, 2H), 1.60 (s, 2H), 0.05-−0.05 (m, 3H). 303456.40 1.32 304 475.10 1.56 305 471.40 1.37 ¹H NMR (400 MHz, CDCl₃) δ8.60 (d, J = 3.9 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 7.14(s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.45 (s,1H), 4.38-4.21 (m, 4H), 4.08 (s, 1H), 3.90 (s, 4H), 3.76 (s, 2H), 2.28(d, J = 91.8 Hz, 2H). 306 473.30 1.82 307 472.30 1.93 308 491.30 1.89309 507.40 1.94 310 497.20 1.19 311 491.00 1.27 312 499.00 1.29 313473.00 1.22 314 541.30 2.06 ¹H NMR (400 MHz, DMSO) δ 7.73 (dd, J = 8.0,7.6 Hz, 1H), 7.20-6.93 (m, 4H), 6.77-6.65 (m, 1H), 5.30 (s, 1H), 4.76(s, 1H), 4.42 (dd, J = 5.3, 3.0 Hz, 2H), 4.33-4.15 (m, 3H), 4.10-3.97(m, 2H), 3.90 (dd, J = 7.2, 5.3 Hz, 1H), 3.80 (s, 3H), 3.76-3.67 (m,1H), 3.66-3.48 (m, 2H), 2.40-2.11 (m, 1H), 2.11-1.82 (m, 2H), 0.96 (d, J= 6.7 Hz, 6H).

Assays for Detecting and Measuring NaV Inhibition Properties of Compound

E-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate.

24 hours before the assay on E-VIPR, HEK cells expressing human NaVsubtype, like NaV 1.7, are seeded in 384-well poly-lysine coated platesat 15,000-20,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest. HEK cellsare grown in media (exact composition is specific to each cell type andNaV subtype) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

Reagents and Solutions

-   -   100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO    -   Compound Plates: 384-well round bottom plate, e.g. Corning        384-well Polypropylene Round Bottom #3656    -   Cell Plates: 384-well tissue culture treated plate, e.g. Greiner        #781091-1B    -   10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO    -   10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO    -   200 mM ABSC1 in H₂0

Bath1 buffer. Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5% β-cyclodextrin (make this prior touse, Sigma #C4767), 8 μM CC2-DMPE+2.5 μM DiSBAC₆(3). To make thesolution Add volume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation is first mix Pluronic andCC2-DMPE, then add DiSBAC₆(3) while vortexing, then addBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spot compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds are added to each well at 160×desired final concentration in neat DMSO. Final compound plate volumewill be 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay is 0.625%.

2) Prepare Hexyl Dye Solution.

3) Prepare cell plates. On the day of the assay, medium is aspirated andcells are washed three times with 100 μL of Bath1 Solution, maintaining25 μL residual volume in each well.

4) Dispense 25 μL per well of Hexyl Dye Solution into cell plates.Incubate for 20-35 minutes at room temp or ambient conditions.

5) Dispense 80 μL per well of Bath1 into compound plates. Acid Yellow-17(1 mM) is added and Potassium Chloride can be altered from 4.5 to 20 mMdepending on the NaV subtype and assay sensitivity.

6) Wash cell plates three times with 100 μL per well of Bath1, leaving25 μL of residual volume. Then transfer 25 uL per well from CompoundPlates to Cell Plates. Incubate for 20-35 minutes at room temp/ambientcondition

7) Read Plate on E-VIPR. Use the current-controlled amplifier to deliverstimulation wave pulses for typically 9 seconds and a scan rate of 400Hz. A pre-stimulus recording is performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform is appliedfor 9 seconds followed by 0.5 seconds of post-stimulation recording toexamine the relaxation to the resting state. The stimulatory waveform ofthe electrical stimulation is specific for each cell type and can varythe magnitude, duration and frequency of the applied current to providean optimal assay signal.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R□□=R_(f)/R_(i) is thencalculated and reported as a function of time.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}{\,^{*}100.}}$

where R is the ratio response of the test compound

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

IonWorks assays.

Sodium currents were recorded using the automated patch clamp system,IonWorks (Molecular Devices Corporation, Inc.). Cells expressing Navsubtypes are harvested from tissue culture and placed in suspension at0.5-4 million cells per mL Bath1. The IonWorks instrument measureschanges in sodium currents in response to applied voltage clampsimilarly to the traditional patch clamp assay, except in a 384-wellformat. Using the IonWorks, dose-response relationships were determinedin voltage clamp mode by depolarizing the cell from the experimentspecific holding potential to a test potential of about 0 mV before andfollowing addition of the test compound. The influence of the compoundon currents are measured at the test potential.

1-Benzazepin-2-One Binding Assay

The sodium channel inhibiting properties of the compounds of theinvention can also be determined by assay methods described in Williams,B. S. et al., “Characterization of a New Class of Potent Inhibitors ofthe Voltage-Gated Sodium Channel NaV 1.7,” Biochemistry, 2007, 46,14693-14703, the entire contents of which are incorporated herein byreference.

The exemplified compounds of Table 1 herein are active against one ormore sodium channels as measured using the assays described herein aboveas presented in Table 4.

TABLE 4 [A1] IC50: +++ <= 2.0 μM < ++ <= 5.0 μM < + Cmpd. No. BinnedActivity Data 1 +++ 2 +++ 3 +++ 4 +++ 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 +13 + 14 ++ 15 ++ 16 ++ 17 ++ 18 ++ 19 ++ 20 ++ 21 ++ 22 ++ 23 ++ 24 ++25 ++ 26 ++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35+++ 36 +++ 37 +++ 38 +++ 39 + 40 +++ 41 +++ 42 +++ 43 ++ 44 +++ 45 +++46 +++ 47 +++ 48 +++ 49 + 50 +++ 51 ++ 52 ++ 53 +++ 54 +++ 55 +++ 56 +++57 + 58 +++ 59 +++ 60 +++ 61 +++ 62 ++ 63 +++ 64 +++ 65 +++ 66 +++ 67+++ 68 +++ 69 +++ 70 +++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 +++ 77+++ 78 +++ 79 +++ 80 +++ 81 ++ 82 +++ 83 +++ 84 +++ 85 +++ 86 +++ 87 +++88 +++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 +++ 95 +++ 96 +++ 97 +++ 98+++ 99 +++ 100 +++ 101 +++ 102 +++ 103 +++ 104 +++ 105 +++ 106 +++ 107+++ 108 +++ 109 +++ 110 +++ 111 +++ 112 +++ 113 +++ 114 +++ 115 +++ 116+++ 117 +++ 118 +++ 119 +++ 120 +++ 121 +++ 122 +++ 123 +++ 124 +++ 125+++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++ 131 +++ 132 +++ 133 +++ 134+++ 135 +++ 136 +++ 137 +++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143+++ 144 +++ 145 +++ 146 +++ 147 +++ 148 +++ 149 +++ 150 +++ 151 +++ 152+++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++ 159 +++ 160 +++ 161+++ 162 +++ 163 +++ 164 +++ 165 +++ 166 +++ 167 +++ 168 +++ 169 +++ 170+++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 +++ 179+++ 180 +++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188+++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196 +++ 197+++ 198 +++ 199 +++ 200 +++ 201 +++ 202 +++ 203 +++ 204 +++ 205 + 206+++ 207 +++ 208 +++ 209 +++ 210 ++ 211 +++ 212 ++ 213 +++ 214 +++ 215+++ 216 +++ 217 ++ 218 +++ 219 + 220 ++ 221 +++ 222 +++ 223 +++ 224 +++225 +++ 226 +++ 227 +++ 228 +++ 229 +++ 230 +++ 231 +++ 232 +++ 233 +++234 +++ 235 +++ 236 +++ 237 +++ 238 +++ 239 +++ 240 +++ 241 ++ 242 243+++ 244 +++ 245 +++ 246 +++ 247 +++ 248 +++ 249 +++ 250 +++ 251 +++ 252+++ 253 +++ 254 +++ 255 +++ 256 +++ 257 +++ 258 +++ 259 +++ 260 +++261 + 262 +++ 263 +++ 264 +++ 265 +++ 266 +++ 267 +++ 268 +++ 269 +++270 +++ 271 +++ 272 +++ 273 +++ 274 +++ 275 +++ 276 + 277 +++ 278 +++279 +++ 280 +++ 281 +++ 282 +++ 283 +++ 284 +++ 285 +++ 286 +++ 287 +++288 +++ 289 +++ 290 + 291 +++ 292 +++ 293 +++ 294 +++ 295 +++ 296 ++297 + 298 +++ 299 +++ 300 +++ 301 +++ 302 +++ 303 +++ 304 +++ 305 +++306 +++ 307 +++ 308 +++ 309 +++ 310 +++ 311 +++ 312 +++ 313 ++ 314 +++

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, ring A is a fused cycloalkyl or heterocycloalkylring; ring B is a substituted or unsubstituted aryl or heteroaryl ring;ring C is a substituted or unsubstituted aryl or heteroaryl ring; R¹ isC1-C6 alkyl, C1-C6 alkoxy, halo, fluoro-C1-C6 alkyl, fluoro-C1-C6alkoxy, or oxo; R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6alkyl, fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂,or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO,CF₂, or NR⁷; R³ is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6alkyl, or fluoro-C1-C6 alkoxy; n, o, and p are integers from 0 to 4inclusive; R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸is H, CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl,heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷.
 2. Thecompound of claim 1, wherein R¹ is C1-C6 alkyl, halo, or oxo.
 3. Thecompound of claim 1 or 2, wherein R¹ is CH₃, F, or oxo.
 4. The compoundof any one of claims 1 to 3, wherein R² is C1-C6 alkyl, C1-C6 alkoxy,fluoro-C1-C6 alkyl, halo, CN, or (C1-C8)-R⁸ wherein up to two CH₂ unitsmay be replaced with O, CO, CF₂, or NR⁷.
 5. The compound of any one ofclaims 1 to 4, wherein R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN, OCH₂CH₂OtBu,OCH₂CH(CH₃)₂.
 6. The compound of any one of claims 1 to 5, wherein R³ isC1-C6 alkyl.
 7. The compound of any one of claims 1 to 6, wherein R³ isCH₃.
 8. The compound of any one of claims 1 to 7, wherein ring A is afused cycloalkyl ring.
 9. The compound of any one of claims 1 to 7,wherein ring A is a fused heterocycloalkyl ring.
 10. The compound ofclaim 8, wherein ring A is


11. The compound of claim 9, wherein ring A is


12. The compound of any one of claims 1 to 11, wherein ring B is an arylring.
 13. The compound of any one of claims 1 to 11, wherein ring B is aheteroaryl ring.
 14. The compound of claim 12, wherein ring B is aphenyl ring.
 15. The compound of claim 14, wherein ring B is


16. The compound of claim 13, wherein ring B is a pyridyl, thiazole,pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole, imidazole,isoxazole, isothiazole, pyridazine, or pyrazine ring.
 17. The compoundof claim 16, wherein ring B is


18. The compound of any one of claims 1 to 17, wherein ring C is asubstituted or unsubstituted aryl ring.
 19. The compound of any one ofclaims 1 to 18, wherein ring C is

wherein: R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, or OH; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷; or two occurrences of R⁴ and R⁵, or R⁵ and R⁶ together with thecarbons to which they are attached form an optionally substituted ringcomprising up to 2 heteroatoms.
 20. The compound of claim 19, wherein R⁴is H, C1-C6 alkoxy, or halo.
 21. The compound of claim 19 or 20, whereinR⁴ is H, OCH₃, or F.
 22. The compound of any one of claims 19 to 21,wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, orfluoro-C1-C6 alkyl.
 23. The compound of any one of claims 19 to 22,wherein R⁵ is H, CH₃, OCH₃, F, Cl, CN, OH, or CF₃.
 24. The compound ofany one of claims 19 to 23, wherein R⁶ is H, C1-C6 alkoxy, fluoro-C1-C6alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain, branched, or cyclic(C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to three CH₂ units may bereplaced with 0, CO, S, SO, SO₂, or NR⁷.
 25. The compound of any one ofclaims 19 to 24, wherein R⁶ is H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂,C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH,OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂,OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃,OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃,OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,


26. The compound of claim 19, wherein R⁴ and R⁵ together with thecarbons to which they are attached form an optionally substituted ringcomprising up to 2 heteroatoms.
 27. The compound of claim 26, whereinring C is


28. The compound of claim 19, wherein R⁵ and R⁶ together with thecarbons to which they are attached form an optionally substituted ringcomprising up to 2 heteroatoms.
 29. The compound of claim 28, whereinring C is


30. The compound of claim 19, wherein

is selected from:


31. The compound of any one of claims 1 to 17, wherein ring C is asubstituted or unsubstituted heteroaryl ring.
 32. The compound of claim31, wherein ring C is a pyridyl or quinoline ring.
 33. The compound ofclaim 31, wherein ring C is selected from:


34. The compound of claim 1, wherein the compound has formula IA:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, ring B is an aryl or heteroaryl ring; R² is C1-C6alkyl, C1-C6 alkoxy, halo, CN, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy,N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up totwo CH₂ units may be replaced with O, CO, CF₂, or NR⁷; o is an integerfrom 0 to 4 inclusive; R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH,OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, orfluoro-C1-C6 alkoxy; R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷,NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂,heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched, orcyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to three CH₂ units maybe replaced with O, CO, S, SO, SO₂, or NR⁷; R⁷ is H, C1-C6 alkyl, CHF₂,CF₃, or C3-C8 cycloalkyl; and R⁸ is H, CF₃, CO₂R⁷, OH, aryl, heteroaryl,C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, orSO₂R⁷.
 35. The compound of claim 34, wherein R² is C1-C6 alkyl, C1-C6alkoxy, fluoro-C1-C6 alkyl, halo, CN, or (C1-C8)-R⁸ wherein up to twoCH₂ units may be replaced with O, CO, CF₂, or NR⁷.
 36. The compound ofclaim 34 or 35, wherein R² is CH₃, OCH₃, CF₃, F, Cl, Br, CN,OCH₂CH₂OtBu, OCH₂CH(CH₃)₂.
 37. The compound of any one of claims 34 to36, wherein ring B is an aryl ring.
 38. The compound of any one ofclaims 34 to 36, wherein ring B is a heteroaryl ring.
 39. The compoundof claim 37, wherein ring B is a phenyl ring.
 40. The compound of claim39, wherein ring B is


41. The compound of claim 38, wherein ring B is a pyridyl, thiazole,pyrimidine, pyrazole, furan, thiophene, pyrrole, oxazole, imidazole,isoxazole, isothiazole, pyridazine, or pyrazine ring.
 42. The compoundof claim 41, wherein ring B is


43. The compound of any one of claims 34 to 42, wherein R⁵ is H, C1-C6alkyl, C1-C6 alkoxy, halo, CN, OH, or fluoro-C1-C6 alkyl.
 44. Thecompound of any one of claims 34 to 43, wherein R⁵ is H, CH₃, OCH₃, F,CN, OH, or CF₃.
 45. The compound of any one of claims 34 to 44, whereinR⁶ is H, C1-C6 alkoxy, fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with 0, CO, S, SO, SO₂, orNR⁷.
 46. The compound of any one of claims 34 to 45, wherein R⁶ is H,OCH₂CH₂CF₃, OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃,CH₂OCH₂CH₂CF₃, C(CH₃)₂OH, OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂,OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂, OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂,SO₂CHF₂, OCH₂CF₂CH₃, OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃,OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃, OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,


47. The compound of any one of claims 34 to 46, wherein

is selected from:


48. The compound of claim 1, wherein the compound has formula IB:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN,fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷,SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replacedwith O, CO, CF₂, or NR⁷; o is an integer from 0 to 4 inclusive; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷; R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl and R⁸ is H,CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl,N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷.
 49. The compound of claim 48,wherein R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo, CN,or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO,CF₂, or NR⁷.
 50. The compound of claim 48 or 49, wherein R² is CH₃,OCH₃, CF₃, F, Cl, Br, CN, OCH₂CH₂OtBu, OCH₂CH(CH₃)₂.
 51. The compound ofany one of claims 48 to 50, wherein R² is F, Cl, or CN.
 52. The compoundof any one of claims 48 to 50, wherein o is 0, 1 or
 2. 53. The compoundof any one of claims 48 to 52, wherein R⁵ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, or fluoro-C1-C6 alkyl.
 54. The compound of any oneof claims 48 to 53, wherein R⁵ is H, CH₃, OCH₃, F, Cl, CN, OH, or CF₃.55. The compound of any one of claims 48 to 54, wherein R⁶ is H, C1-C6alkoxy, fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain,branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with 0, CO, S, SO, SO₂, or NR⁷.
 56. Thecompound of any one of claims 48 to 55, wherein R⁶ is H, OCH₂CH₂CF₃,OCH₂CF(CH₃)₂, C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃,C(CH₃)₂OH, OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH,OCH₂CF₂CHF₂, OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃,OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃,OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,


57. The compound of any one of claims 48 to 56, wherein

is selected from:


58. The compound of claim 1, wherein the compound has formula IC:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence, R² is C1-C6 alkyl, C1-C6 alkoxy, halo, CN,fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, CO₂R⁷,SO₂N(R⁷)₂, or (C1-C8)-R⁸ wherein up to two CH₂ units may be replacedwith O, CO, CF₂, or NR⁷; o is an integer from 0 to 4 inclusive; R⁵ is H,C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷,CO₂R⁷, SO₂N(R⁷)₂, fluoro-C1-C6 alkyl, or fluoro-C1-C6 alkoxy; R⁶ is H,C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷; R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl; and R⁸ is H,CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl,N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷.
 59. The compound of claim 58,wherein R² is C1-C6 alkyl, C1-C6 alkoxy, fluoro-C1-C6 alkyl, halo, CN,or (C1-C8)-R⁸ wherein up to two CH₂ units may be replaced with O, CO,CF₂, or NR⁷.
 60. The compound of claim 58 or 59, wherein R² is CH₃,OCH₃, CF₃, F, Cl, Br, CN, OCH₂CH₂OtBu, OCH₂CH(CH₃)₂.
 61. The compound ofany one of claims 58 to 60, wherein o is 0, 1, or
 2. 62. The compound ofany one of claims 58 to 61, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy,halo, CN, OH, or fluoro-C1-C6 alkyl.
 63. The compound of any one ofclaims 58 to 62, wherein R⁵ is H, CH₃, OCH₃, F, CN, OH, or CF₃.
 64. Thecompound of any one of claims 58 to 63, wherein R⁶ is H, C1-C6 alkoxy,fluoro-C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, or a straight chain, branched, orcyclic (C1-C8)-R⁸ or fluoro-(C1-C8)-R⁸ wherein up to three CH₂ units maybe replaced with 0, CO, S, SO, SO₂, or NR⁷.
 65. The compound of any oneof claims 58 to 64, wherein R⁶ is H, OCH₂CH₂CF₃, OCH₂CF(CH₃)₂,C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH(CH₃)CF₃, CH₂OCH₂CH₂CF₃, C(CH₃)₂OH,OCH₂CH₂OtBu, CH₂C(CH₃)₂OH, OCH(CH₃)₂, OCH₂C(CH₃)₂OH, OCH₂CF₂CHF₂,OCH₂CF₃, OCH₂CH₂OCF₃, OCH(CH₃)CF₂CHF₂, SO₂CHF₂, OCH₂CF₂CH₃,OCH₂CH₂OCH₂CF₃, OCH₂CF₃, OCH₂C(CH₃)₃, OCH₂CH(CH₃)CH₂CF₃, SO₂CH₂CH₃,OCH(CH₃)CH₂CF₃, OCH₂CF₂CHF₂,


66. The compound of any one of claims 58 to 65, wherein

is selected from:


67. The compound of claim 1, wherein the compound is selected from TABLE2

315

316

317

318

319

320

321

322

323

324

325

326

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328

329

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331

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531

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541

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611

612

613

614

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616

617

618

619

620

621

622

623

624

625

626

627

628


69. The compound of claim 1, wherein the compound is selected from TABLE1 1

2

3

4

5

6

7

8

9

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20

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313

314


69. A pharmaceutical composition comprising the compound of any one ofclaims 1 to 68 and a pharmaceutically acceptable carrier.
 70. A methodof inhibiting a voltage-gated sodium ion channel in: a patient; or abiological sample; comprising administering to the patient, orcontacting the biological sample, with the compound or composition ofany one of claims 1 to
 69. 71. The method of claim 70, wherein thevoltage-gated sodium ion channel is NaV 1.7.
 72. A method of treating orlessening the severity of the pain in a subject afflicted with acute,chronic, neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress- or exercise induced angina,palpitations, hypertension, migraine, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound orcomposition of any one of claims 1 to
 69. 73. The method according toclaim 72, wherein said method is used for treating or lessening theseverity of the pain in a subject afflicted with femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; neuropathic low back pain;myofascial pain syndrome; fibromyalgia; temporomandibular joint pain;chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic andacute headache pain; migraine; tension headache, cluster headaches;chronic and acute neuropathic pain, post-herpatic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, abdominal pain; pyelonephritis; appendicitis;cholecystitis; intestinal obstruction; hernias; chest pain, cardiacpain; pelvic pain, renal colic pain, acute obstetric pain, labor pain;cesarean section pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, endometriosis; acute herpes zoster pain; sickle cellanemia; acute pancreatitis; breakthrough pain; orofacial pain, sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, urinary incontinence; hyperactivity bladder; painful bladdersyndrome; interstitial cyctitis (IC); prostatitis; complex regional painsyndrome (CRPS), type I and type II; widespread pain, paroxysmal extremepain, pruritis, tinnitis, or angina-induced pain.